70 results on '"Tomoya, Yamashita"'
Search Results
2. Gut Microbiota Influence the Development of Abdominal Aortic Aneurysm by Suppressing Macrophage Accumulation in Mice
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Ryohei Shinohara, Hitomi Nakashima, Takuo Emoto, Tomoya Yamashita, Yoshihiro Saito, Naofumi Yoshida, Taishi Inoue, Katsuhiro Yamanaka, Kenji Okada, and Ken-ichi Hirata
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Male ,Mice ,Disease Models, Animal ,Apolipoproteins E ,Cholesterol ,abdominal aortic aneurysm ,gut microbiota ,Macrophages ,Internal Medicine ,Animals ,Aorta, Abdominal ,Aortic Aneurysm, Abdominal ,Gastrointestinal Microbiome - Abstract
Background: Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease characterized by dilated abdominal aorta. Immune cells have been shown to contribute to the development of AAA, and that the gut microbiota is associated with numerous diseases, including cardiovascular diseases, by regulating immune systems or metabolic pathways of the host. However, the interaction between the gut microbiota and AAA remains unknown. Methods: Apolipoprotein E–deficient male mice were fed a high-cholesterol diet and divided into three groups: the control group was maintained under normal water (control group), the oral AVNM group was maintained under drinking water supplemented with ampicillin, vancomycin, neomycin, and metronidazole, and the i.p. AVNM group was injected AVNM intraperitoneally. After 1 week of pretreatment with antibiotics, these mice were administrated Ang II via subcutaneous osmotic pumps for 4 weeks and euthanized to evaluate AAA formation. Results: Depletion of gut microbiota by oral AVNM ameliorated the incidence of AAAs (control group: 58.9% versus oral AVNM group: 28.6% versus i.p. AVNM group: 75.0%, P = 0.0005) and prevented death due to ruptured aneurysms (control group: 11% versus oral AVNM group: 0% versus i.p. AVNM group: 15%). Oral AVNM suppressed monocyte storage in the spleen, but not in other organs. Despite possessing a higher level of cholesterol, recruitment of monocytes into the suprarenal aorta was suppressed in the oral AVNM group. In AVNM drinking mice, NOD1 ligand, a kind of PRR ligands, increased the development of AAAs and accumulation of macrophages in the aortae. Conclusions: The gut microbiota plays a critical role in AAA formation. Therefore, regulation of the microbiota or the immune system can be a therapeutic approach for AAA.
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- 2022
3. Circulating intermediate monocytes and atrial structural remodeling associated with atrial fibrillation recurrence after catheter ablation
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Naofumi Yoshida, Koji Fukuzawa, Hideya Suehiro, Tomoya Yamashita, Hiroyuki Takahara, Yu Izawa, Yoshiaki Watanabe, Yusuke Sonoda, Toshihiro Nakamura, Kyoko Yamamoto, Makoto Takemoto, Tomomi Akita, Jun Sakai, Ken-ichi Hirata, Mitsuru Takami, Kunihiko Kiuchi, Kazutaka Nakasone, and Atsusuke Yatomi
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medicine.medical_specialty ,medicine.medical_treatment ,CD14 ,Contrast Media ,Gadolinium ,Catheter ablation ,030204 cardiovascular system & hematology ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,hemic and lymphatic diseases ,Physiology (medical) ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,Heart Atria ,cardiovascular diseases ,030212 general & internal medicine ,Univariate analysis ,medicine.diagnostic_test ,Receiver operating characteristic ,Surrogate endpoint ,business.industry ,Magnetic resonance imaging ,Atrial fibrillation ,Atrial Remodeling ,Ablation ,medicine.disease ,Magnetic Resonance Imaging ,Catheter Ablation ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,human activities - Abstract
Background Inflammation, such as that associated with intermediate CD14++ CD16+ monocytes and atrial structural remodeling (SRM), may be important in the recurrence of atrial fibrillation (AF) after catheter ablation. However, the relationship between the intermediate CD14++ CD16+ monocytes, SRM, and AF recurrence is unclear. Methods Twenty-four patients with AF were enrolled. The proportion of intermediate monocytes (PIM) was assessed before ablation by flow cytometry. As a surrogate marker of SRM, the volume ratio (VR) of signal intensity greater than 1 standard deviation on late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) was calculated. We investigated whether PIM correlated with SRM on LGE-MRI and determined the optimal cutoff value for predicting AF recurrence. Results Univariate analysis revealed positive correlations between PIM and BNP with SRM (PIM: r = .593, p = .002; BNP: r = .567, p = .004). Multivariable analysis revealed that PIM was independently associated with VR on LGE-MRI (β = .522; p = .033). The finding of an area under the receiver operating characteristic curve of 0.750 revealed that a VR ≥ 13.3% on LGE-MRI as the optimal cutoff value to predict AF recurrence with 80% sensitivity and 71% specificity, which was associated with PIM ≥ 10.0%. Conclusion Intermediate monocytes were significantly positively correlated with SRM. PIM ≥ 10% was associated with a VR ≥ 13.3% on LGE-MRI, which predicted AF recurrence after catheter ablation.
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- 2021
4. Metabolic alterations in plasma after laparoscopic sleeve gastrectomy
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Hitomi Nakashima, Naofumi Yoshida, Wataru Ogawa, Ken-ichi Hirata, Tetsuya Takahashi, Yoshihiro Saito, Yushi Hirota, Seiichi Kitahama, Tokiko Tabata, Tomoya Yamashita, Yasuko Hirono, Ryohei Shinohara, and Takuo Emoto
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Male ,0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Metabolite ,Short Report ,030209 endocrinology & metabolism ,Body Mass Index ,Plasma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gastrectomy ,Weight loss ,Diabetes mellitus ,Internal medicine ,Metabolites ,Internal Medicine ,medicine ,Humans ,Choline ,Obesity ,chemistry.chemical_classification ,business.industry ,Articles ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Obesity, Morbid ,Amino acid ,Laparoscopic sleeve gastrectomy ,Citric acid cycle ,Clinical Science and Care ,030104 developmental biology ,Endocrinology ,chemistry ,Succinic acid ,Female ,Laparoscopy ,Malic acid ,medicine.symptom ,business ,Follow-Up Studies - Abstract
Laparoscopic sleeve gastrectomy (LSG) is an important therapeutic option for morbidly obese patients. Although LSG promotes sufficient weight loss, how LSG changes plasma metabolites remains unclear. We assessed changes in plasma metabolite levels after LSG. We collected plasma samples from 15 morbidly obese Japanese patients before and 3 months after LSG. A total of 48 metabolites were quantified using capillary electrophoresis time‐of‐flight mass spectrometry‐based metabolomic profiling. Branched chain amino acids, several essential amino acids, choline, 2‐hydroxybutyric acid, 2‐oxoisovaleric acid and hypoxanthine were significantly decreased after LSG. Tricarboxylic acid cycle metabolites, including citric acid, succinic acid and malic acid, were significantly elevated after LSG. This is the first report to show dynamic alterations in plasma metabolite concentrations, as assessed using capillary electrophoresis time‐of‐flight mass spectrometry, in morbidly obese patients after LSG. Our results might show how LSG helps improve obesity, in part through metabolic status changes, and propose novel therapeutic targets to ameliorate obesity., Dynamic alterations in plasma metabolite concentrations in morbidly obese patients after laparoscopic sleeve gastrectomy.
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- 2020
5. Circulating intermediate monocytes and toll-like receptor 4 correlate with low-voltage zones in atrial fibrillation
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Tokiko Tabata, Tomoya Yamashita, Jun Sakai, Atsusuke Yatomi, Makoto Takemoto, Hideya Suehiro, Yusuke Sonoda, Atsushi Suzuki, Toshihiro Nakamura, Koji Fukuzawa, Tomomi Akita, Kyoko Yamamoto, Ken-ichi Hirata, Mitsuru Takami, Kazutake Nakasone, Naofumi Yoshida, Hiroyuki Takahara, and Kunihiko Kiuchi
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Male ,medicine.medical_specialty ,CD14 ,Lipopolysaccharide Receptors ,Action Potentials ,Inflammation ,030204 cardiovascular system & hematology ,CD16 ,GPI-Linked Proteins ,Monocytes ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Internal medicine ,Atrial Fibrillation ,Humans ,Medicine ,Prospective Studies ,030212 general & internal medicine ,Receptor ,Aged ,Toll-like receptor ,business.industry ,Receptors, IgG ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Toll-Like Receptor 4 ,Endocrinology ,TLR4 ,Female ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Inflammation has been suggested to play a key role in the pathogenesis of atrial fibrillation (AF). Our hypothesis was that this inflammation, mediated by intermediate monocytes and toll-like receptor 4 (TLR4), causes the formation and expansion of low-voltage zones (LVZs). Prior to ablation, the monocyte subsets of 78 AF patients and TLR4 expression of 66 AF patients were analyzed via a flow cytometric analysis. Based on the CD14/CD16 expression, the monocytes were divided into three subsets: classical, intermediate, and non-classical. At the beginning of the ablation session, voltage mapping was performed. LVZs were defined as all bipolar electrogram amplitudes of
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- 2020
6. Unraveling the Effects of Trimethylamine N-Oxide on Stroke: 'The lower, the better?'
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Ken-ichi Hirata, Tomoya Yamashita, Takuo Emoto, and Naofumi Yoshida
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medicine.medical_specialty ,Trimethylamine N-oxide ,Choline ,Methylamines ,chemistry.chemical_compound ,Text mining ,Risk Factors ,Carnitine ,Internal medicine ,Internal Medicine ,Humans ,Medicine ,Stroke ,Ischemic Stroke ,Lipotropic Agents ,business.industry ,Biochemistry (medical) ,Oxidants ,medicine.disease ,Gastrointestinal Microbiome ,Betaine ,Editorial ,Cholesterol ,Liver ,chemistry ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Diet Therapy - Published
- 2021
7. Effect of Resistant Starch on the Gut Microbiota and Its Metabolites in Patients with Coronary Artery Disease
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Tomoya Yamashita, Naofumi Yoshida, Akihiko Kondo, Daisuke Sasaki, Tokiko Tabata, Hajime Fukuda, Ro Osawa, Tomohiro Hayashi, Kengo Sasaki, and Ken-ichi Hirata
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Male ,food.ingredient ,Butyrate ,Gut microbiota ,030204 cardiovascular system & hematology ,Biology ,Gut flora ,digestive system ,Coronary artery disease ,Microbiology ,Feces ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,food ,RNA, Ribosomal, 16S ,Internal Medicine ,Humans ,Bacteroides ,Resistant starch ,Aged ,Bacteria ,Biochemistry (medical) ,Starch ,Middle Aged ,Ribosomal RNA ,Fatty Acids, Volatile ,Prognosis ,biology.organism_classification ,Gastrointestinal Microbiome ,Real-time polymerase chain reaction ,Original Article ,Female ,Fermentation ,Cardiology and Cardiovascular Medicine ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Aim: Bacteroides vulgatus and B. dorei have a protective effect against atherosclerosis, suggesting that expansion of these species in the gut microbiota could help patients with coronary artery disease (CAD). This study aimed to investigate the effect of resistant starch (RS) on the gut microbiota and its metabolites in fecal sample cultures from patients with CAD and individuals without CAD, using a single-batch fermentation system. Methods: Fecal samples from 11 patients with CAD and 10 individuals without CAD were fermented for 30 h with or without RS in the Kobe University Human Intestinal Microbiota Model (KUHIMM). Gut microbiota and the abundance of B. vulgatus and B. dorei were analyzed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing and the quantitative polymerase chain reaction. Short-chain fatty acids were analyzed using high-performance liquid chromatography. Results: Gut microbial analysis showed significantly lower levels of B. vulgatus and B. dorei in the original fecal samples from patients with CAD, which was simulated after 30 h of fermentation in the KUHIMM. Although RS significantly increased the absolute numbers of B. vulgatus and B. dorei, and butyrate levels in CAD fecal sample cultures, the numbers varied among each patient. Conclusions: The effect of RS on gut microbiota and its metabolites in the KUHIMM varied between CAD and non-CAD fecal sample cultures. The KUHIMM may be useful for preclinical evaluations of the effects of RS on the gut microbiota and its metabolites.
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- 2019
8. Gut Microbiome and Plasma Microbiome-Related Metabolites in Patients With Decompensated and Compensated Heart Failure
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Wataru Ogawa, Ryuji Toh, Kenjiro Kami, Tokiko Tabata, Naofumi Yoshida, Naoto Sasaki, Ken-ichi Hirata, Takuo Emoto, Yasuhiro Irino, Masakazu Shinohara, Tomohiro Hayashi, Takuji Yamada, Yuko Okada, Tomoya Yamashita, Hikaru Watanabe, and Taiji Mizoguchi
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Male ,0301 basic medicine ,medicine.medical_specialty ,Metabolite ,030204 cardiovascular system & hematology ,Gut flora ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Escherichia ,Metabolites ,Escherichia coli ,medicine ,Humans ,Shigella ,Microbiome ,Aged ,Aged, 80 and over ,Heart Failure ,Gut microbiome ,biology ,Gastrointestinal Microbiome ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,Endocrinology ,chemistry ,Heart failure ,Female ,Bifidobacterium ,Cardiology and Cardiovascular Medicine - Abstract
Background Gut microbiome composition or circulating microbiome-related metabolites in patients with heart failure (HF) have not been investigated at different time points (i.e., in the decompensated (Decomp) and compensated (Comp) phases). Methods and Results: We prospectively enrolled 22 patients admitted for HF and 11 age-, sex-, and comorbidity-matched hospitalized control subjects without a history of HF. Gut flora and plasma microbiome-related metabolites were evaluated by amplicon sequencing of the bacterial 16S ribosomal RNA gene and capillary electrophoresis time-of-flight mass spectrometry, respectively. HF patients were evaluated in both the Decomp and Comp phases during hospitalization. The phylum Actinobacteria was enriched in HF patients compared with control subjects. At the genus level, Bifiodobacterium was abundant while Megamonas was depleted in HF patients. Meanwhile, plasma concentration of trimethylamine N-oxide (TMAO), a gut microbiome-derived metabolite, was increased in HF patients (Decomp HF vs. control, P=0.003; Comp HF vs. control, P=0.004). A correlation analysis revealed positive correlations between the abundance of the genus Escherichia/Shigella and levels of TMAO and indoxyl sulfate (IS, a microbe-dependent uremic toxin) in Comp HF (TMAO: r=0.62, P=0.002; IS: r=0.63, P=0.002). Escherichia/Shigella was more abundant in Decomp than in Comp HF (P=0.030). Conclusions Our results suggest that gut microbiome composition and microbiome-related metabolites are altered in HF patients.
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- 2018
9. The Gut Microbiome as a Promising Biomarker of Cancer Progression Among Female Never-smokers With Lung Adenocarcinoma
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Yoshimasa Maniwa, Takehiro Otoshi, Kenji Mizuguchi, Motoko Tachihara, Jonguk Park, Yoshihiro Nishimura, Tomoo Itoh, Kazuyuki Kobayashi, Tomoya Yamashita, Tatsuya Nagano, Yugo Tanaka, Koji Hosomi, Tokiko Tabata, Reina Sekiya, and Jun Kunisawa
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Oncology ,medicine.medical_specialty ,Lung ,business.industry ,Cancer ,medicine.disease ,Gut microbiome ,Never smokers ,medicine.anatomical_structure ,Internal medicine ,medicine ,Biomarker (medicine) ,Adenocarcinoma ,business - Abstract
Background: The gut microbiome plays an important role in the immune system and has attracted attention as a biomarker of various diseases, including cancer. As such, we examined the relationship between the gut microbiome and lung cancer progression. In addition, we assessed the correlation between the gut microbiome and epidermal growth factor receptor (EGFR) mutation status.Methods: Female never-smokers diagnosed with lung adenocarcinoma were consecutively and prospectively enrolled between May 2018 and August 2019. Fecal samples were collected within 1 month before or after diagnosis and before administration of any lung cancer treatment. Principal coordinate analyses were retrospectively performed using Bray-Curtis distance matrices to investigate the effects of clinical variables (age, body mass index, Tumor-Node-Metastasis stage, T category, N category, M category, primary tumor size, performance status, and EGFR mutation status) on the gut microbial community. A correlation analysis was also performed to determine the strength of association between the dominant taxonomy (comprising ≥1% of the relative abundance of bacterial DNA sequences) and clinical variables.Results: A total of 37 patients were enrolled. T category and primary tumor size were significantly correlated with the gut microbial community (p=0.018 and 0.041, respectively). At the genus level, a significant positive correlation was observed between the relative abundance of Faecalibacterium and both T category (correlation coefficient, R=0.51, p=0.0013) and primary tumor size (R=0.37, p=0.024), whereas a significant negative correlation was observed between the relative abundances of Fusicatenibacter and Bacteroides and T category (R=−0.35, p=0.034 and R=−0.32, p=0.05, respectively) and primary tumor size (R=−0.36, p=0.029 and R=−0.41, p=0.012, respectively). EGFR mutation status had no statistically significant effect on the gut microbial community (p=0.11). However, the relative abundances of Bifidobacterium and Faecalibacterium were significantly higher in EGFR mutation–negative patients than EGFR mutation–positive patients (p=0.012 and 0.041), whereas the relative abundance of Blautia was significantly lower in EGFR mutation–negative patients (p=0.036).Conclusions: This is the first study identifying the gut microbiome as a promising biomarker of lung cancer progression. Further elucidation of the role of the gut microbiome in lung cancer progression could facilitate development of new treatments for lung cancer.
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- 2021
10. Short- versus long-segment posterior spinal fusion with vertebroplasty for osteoporotic vertebral collapse with neurological impairment in thoracolumbar spine: a multicenter study
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Tomohiro Izumi, Daisuke Sakai, Masayuki Ohashi, Ken Ishii, Toshinori Tsukanishi, Masashi Oshima, Hideki Murakami, Michio Hongo, Masayuki Shimizu, Hirooki Endo, Katsumi Harimaya, Shinji Adachi, Kei Ando, Akira Iwata, Seiji Ueda, Kei Watanabe, Shota Ikegami, Katsuhito Kiyasu, Kazuyoshi Kobayashi, Nobuhiko Yokoyama, Sumihisa Orita, Toshimasa Futatsugi, Tomoya Yamashita, Hidetomi Terai, Yuji Matsuoka, Norihiro Isogai, Kazuyoshi Nakanishi, Masayuki Miyagi, Yuta Shiono, Shiro Imagama, Hiroyasu Fujiwara, Haruki Funao, Koji Tamai, Toru Hirano, Yuya Ishikawa, Yukitaka Nagamoto, Kenichiro Kakutani, Tetsuya Abe, Kenichi Kawaguchi, Keiichi Katsumi, Tomohiro Hikata, Kota Watanabe, Yasuchika Aoki, Satoshi Suzuki, Toshitaka Yoshii, Shoji Seki, Kenya Nojiri, Eijiro Okada, Hirosuke Nishimura, Hidekazu Suzuki, Toshiro Doi, Naoto Endo, Shuta Ushio, Atsushi Nakano, Takashi Yurube, Hidekazu Oishi, Katsuhito Yoshioka, Yohei Shibuya, Tadashi Nukaga, Naobumi Hosogane, Gen Inoue, Masahiko Takahata, Takashi Kaito, Shuta Yamada, Seiji Ohtori, Atsushi Tagami, Takeo Furuya, Wataru Saito, Atsushi Kimura, and Hirokazu Inoue
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Male ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Posterior spinal fusion ,Long-segment ,Sports medicine ,medicine.medical_treatment ,Kyphosis ,Thoracic Vertebrae ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Thoracolumbar spine ,Internal medicine ,Epidemiology ,medicine ,Humans ,Orthopedics and Sports Medicine ,Osteoporotic vertebral collapse ,Aged ,Retrospective Studies ,030222 orthopedics ,Vertebroplasty ,Rehabilitation ,Lumbar Vertebrae ,business.industry ,Correction loss ,Short-segment ,Pain scale ,medicine.disease ,Decompression, Surgical ,Surgery ,Spinal Fusion ,Treatment Outcome ,Spinal fusion ,Orthopedic surgery ,Spinal Fractures ,Female ,Vertebral fracture ,lcsh:RC925-935 ,business ,030217 neurology & neurosurgery ,Osteoporotic Fractures ,Research Article - Abstract
Background Vertebroplasty with posterior spinal fusion (VP + PSF) is one of the most widely accepted surgical techniques for treating osteoporotic vertebral collapse (OVC). Nevertheless, the effect of the extent of fusion on surgical outcomes remains to be established. This study aimed to evaluate the surgical outcomes of short- versus long-segment VP + PSF for OVC with neurological impairment in thoracolumbar spine. Methods We retrospectively collected data from 133 patients (median age, 77 years; 42 men and 91 women) from 27 university hospitals and their affiliated hospitals. We divided patients into two groups: a short-segment fusion group (S group) with 2- or 3-segment fusion (87 patients) and a long-segment fusion group (L group) with 4- through 6-segment fusion (46 patients). Surgical invasion, clinical outcomes, local kyphosis angle (LKA), and complications were evaluated. Results No significant differences between the two groups were observed in terms of neurological recovery, pain scale scores, and complications. Surgical time was shorter and blood loss was less in the S group, whereas LKA at the final follow-up and correction loss were superior in the L group. Conclusion Although less invasiveness and validity of pain and neurological relief are secured by short-segment VP + PSF, surgeons should be cautious regarding correction loss.
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- 2020
11. Effect of bisphosphonates or teriparatide on mechanical complications after posterior instrumented fusion for osteoporotic vertebral fracture: a multi-center retrospective study
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Yasuchika Aoki, Masayuki Shimizu, Masayuki Ohashi, Hirooki Endo, Katsumi Harimaya, Syuta Yamada, Toshinori Tsukanishi, Koji Tamai, Tomoya Yamashita, Hirosuke Nishimura, Yuta Shiono, Ken Ishii, Eijiro Okada, Michio Hongo, Katsuhito Kiyasu, Hidekazu Suzuki, Masashi Oshima, Norihiro Isogai, Masayuki Miyagi, Shinji Adachi, Kei Watanabe, Shoji Seki, Atsuyuki Kawabata, Tadashi Nukaga, Kei Ando, Seiji Ohtori, Kazuyoshi Kobayashi, Hidetomi Terai, Haruki Funao, Kenya Nojiri, Akira Iwata, Toshitaka Yoshii, Shuta Ushio, Nobuhiko Yokoyama, Atsushi Nakano, Seiji Ueda, Shota Ikegami, Toshimasa Futatsugi, Hidekazu Oishi, Takeo Furuya, Takashi Yurube, Katsuhito Yoshioka, Atsushi Tagami, Daisuke Sakai, Kota Watanabe, Takashi Hirai, Yuji Matsuoka, Keiichi Katsumi, Kazuyoshi Nakanishi, Kenichiro Kakutani, Tetsuya Abe, Hiroyasu Fujiwara, Tomohiro Hikata, Hideki Murakami, Gen Inoue, Yukitaka Nagamoto, Naobumi Hosogane, Masahiko Takahata, Takashi Kaito, Toshiro Doi, Satoshi Suzuki, Yohei Shibuya, Hirokazu Inoue, Sumihisa Orita, Wataru Saito, Shiro Imagama, Atsushi Kimura, and Kenichi Kawaguchi
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Male ,Reoperation ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Visual analogue scale ,Osteoporosis ,030209 endocrinology & metabolism ,03 medical and health sciences ,0302 clinical medicine ,Lumbar ,Japan ,Rheumatology ,Teriparatide ,Internal medicine ,medicine ,Humans ,Orthopedics and Sports Medicine ,Primary osteoporosis ,Glucocorticoids ,Aged ,Retrospective Studies ,Aged, 80 and over ,Glucocorticoid-induced osteoporosis ,Bone Density Conservation Agents ,Diphosphonates ,business.industry ,Retrospective cohort study ,Bisphosphonates ,medicine.disease ,Surgery ,Pseudarthrosis ,Spinal Fusion ,Orthopedic surgery ,Spinal Fractures ,Female ,Osteoporotic vertebral fractures ,lcsh:RC925-935 ,business ,Complication ,Osteoporotic Fractures ,030217 neurology & neurosurgery ,Research Article ,medicine.drug - Abstract
Background The optimal treatment of osteoporosis after reconstruction surgery for osteoporotic vertebral fractures (OVF) remains unclear. In this multicentre retrospective study, we investigated the effects of typically used agents for osteoporosis, namely, bisphosphonates (BP) and teriparatide (TP), on surgical results in patients with osteoporotic vertebral fractures. Methods Retrospectively registered data were collected from 27 universities and affiliated hospitals in Japan. We compared the effects of BP vs TP on postoperative mechanical complication rates, implant-related reoperation rates, and clinical outcomes in patients who underwent posterior instrumented fusion for OVF. Data were analysed according to whether the osteoporosis was primary or glucocorticoid-induced. Results A total of 159 patients who underwent posterior instrumented fusion for OVF were included. The overall mechanical complication rate was significantly lower in the TP group than in the BP group (BP vs TP: 73.1% vs 58.2%, p = 0.045). The screw backout rate was significantly lower and the rates of new vertebral fractures and pseudoarthrosis tended to be lower in the TP group than in the BP group. However, there were no significant differences in lumbar functional scores and visual analogue scale pain scores or in implant-related reoperation rates between the two groups. The incidence of pseudoarthrosis was significantly higher in patients with glucocorticoid-induced osteoporosis (GIOP) than in those with primary osteoporosis; however, the pseudoarthrosis rate was reduced by using TP. The use of TP also tended to reduce the overall mechanical complication rate in both primary osteoporosis and GIOP. Conclusions The overall mechanical complication rate was lower in patients who received TP than in those who received a BP postoperatively, regardless of type of osteoporosis. The incidence of pseudoarthrosis was significantly higher in patients with GIOP, but the use of TP reduced the rate of pseudoarthrosis in GIOP patients. The use of TP was effective to reduce postoperative complications for OVF patients treated with posterior fusion.
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- 2020
12. Data on impact of monocytes and glucose fluctuation on plaque vulnerability in patients with coronary artery disease
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Kenzo Uzu, Wataru Ogawa, Kenichi Yanaka, Hachidai Takahashi, Takuo Emoto, Natsuko Tahara, Takayoshi Toba, Naoto Sasaki, Hiromasa Otake, Yuichiro Nagano, Naofumi Yoshida, Hiroyuki Yamamoto, Daisuke Terashita, Yushi Hirota, Masaru Kuroda, Kouji Kuroda, Yuto Shinkura, Yoshiro Tsukiyama, Yoshinori Nagasawa, Ken-ichi Hirata, Kazuhiko Sakaguchi, Tomoya Yamashita, and Toshiro Shinke
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0301 basic medicine ,medicine.medical_specialty ,Multidisciplinary ,business.industry ,CD14 ,030204 cardiovascular system & hematology ,CD16 ,Medicine and Dentistry ,lcsh:Computer applications to medicine. Medical informatics ,medicine.disease ,Coronary artery disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Coronary plaque ,medicine ,Cardiology ,lcsh:R858-859.7 ,Population study ,Research article ,In patient ,lcsh:Science (General) ,business ,lcsh:Q1-390 - Abstract
Data presented in this article are supplementary material to our research article entitled “Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients” [1]. This article contains the data of study population, diagnostic ability of CD14++CD16+ monocytes to identify thin-cap fibroatheromas, and association between laboratory variables and plaque properties.
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- 2018
13. Impact of CD14 ++ CD16 + monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients
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Wataru Ogawa, Takayoshi Toba, Tomoya Yamashita, Kenichi Yanaka, Kazuhiko Sakaguchi, Kenzo Uzu, Yuichiro Nagano, Toshiro Shinke, Hiromasa Otake, Natsuko Tahara, Naofumi Yoshida, Yoshinori Nagasawa, Hachidai Takahashi, Hiroyuki Yamamoto, Yushi Hirota, Daisuke Terashita, Masaru Kuroda, Takuo Emoto, Kouji Kuroda, Yuto Shinkura, Naoto Sasaki, Ken-ichi Hirata, and Yoshiro Tsukiyama
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0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,CD14 ,Monocyte ,Fibrous cap ,030204 cardiovascular system & hematology ,CD16 ,medicine.disease ,Coronary artery disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Optical coherence tomography ,Internal medicine ,Diabetes mellitus ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Glycemic - Abstract
Background and aims This study examined the impact of CD14++CD16+ monocytes on coronary plaque vulnerability, as assessed by optical coherence tomography (OCT), and investigated their association with daily glucose fluctuation. Although increased CD14++CD16+ monocyte levels have been reported to increase cardiovascular events, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without diabetes mellitus (DM) remains unclear. Methods This prospective observational study included 50 consecutive patients with CAD, receiving lipid-lowering therapy and undergoing coronary angiography and OCT. Patients were divided into 3 tertiles according to the CD14++CD16+ monocyte percentages assessed by flow cytometry. Standard OCT parameters were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30–70%). Daily glucose fluctuation was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results CD14++CD16+ monocytes negatively correlated with fibrous cap thickness (r = −0.508, p Conclusions CD14++CD16+ monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14++CD16+ monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14++CD16+ monocytes could be a possible therapeutic target for coronary plaque stabilization.
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- 2018
14. Efficacy of Ninjin'yoeito in treating severe coronavirus disease 2019 in patients in an intensive care unit
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Tomoya Yamashita, Takaya Morooka, Akihiro Fuke, Naoki Aomatsu, Katsumi Ikeda, Michinori Shirano, Junichi Ishikawa, Ayumu Tsuruoka, Koka Motoyama, Hiroshi Rinka, Kiyoshi Maeda, Hidenori Nakagawa, Daiki Kitagawa, and Kazuaki Shigemitsu
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Male ,medicine.medical_treatment ,Comorbidity ,law.invention ,Endocrinology ,Japan ,law ,Ninjin'yoeito ,Aged, 80 and over ,Mortality rate ,Prognostic nutritional index ,General Medicine ,Middle Aged ,Combined Modality Therapy ,Intensive care unit ,Intensive Care Units ,Kampo ,Treatment Outcome ,Neurology ,Cardiovascular Diseases ,Female ,Kidney Diseases ,Median body ,Adult ,medicine.medical_specialty ,Article ,Cellular and Molecular Neuroscience ,Enteral Nutrition ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,medicine ,Humans ,Aged ,Mechanical ventilation ,SARS-CoV-2 ,Endocrine and Autonomic Systems ,business.industry ,COVID-19 ,Pneumonia ,Length of Stay ,medicine.disease ,Respiration, Artificial ,COVID-19 Drug Treatment ,Nutrition Assessment ,Parenteral nutrition ,Medicine, Kampo ,business ,Drugs, Chinese Herbal ,Kidney disease - Abstract
Coronavirus Disease-2019 (COVID-19), an infectious disease associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global emergency with high mortality. There are few effective treatments, and many severe patients are treated in an intensive care unit (ICU). The purpose of this study was to evaluate whether the Japanese Kampo medicine ninjin'yoeito (NYT) is effective in treating ICU patients with COVID-19. Nine patients with confirmed SARS-CoV-2 infection admitted to the ICU were enrolled in this study. All patients underwent respiratory management with invasive mechanical ventilation (IMV) and enteral nutrition. Four patients received NYT (7.5 g daily) from an elemental diet tube. We retrospectively examined the prognostic nutritional index (PNI), length of IMV, length of ICU stay, length of hospital stay, rate of tracheostomy, and mortality rate. The median age of the enrolled participants was 60.0 years (4 men and 5 women). The median body mass index was 27.6. The most common comorbidity was diabetes (4 patients, 44%), followed by hypertension (3 patients, 33%) and chronic kidney disease (2 patients, 22%). The median length of IMV, ICU stay, and hospital stay were all shorter in the NYT group than in the non-NYT group (IMV; 4.0 days vs 14.3 days, ICU; 5.3 days vs 14.5 days, hospital stay; 19.9 days vs 28.2 days). In the NYT and non-NYT groups, the median PNI at admission was 29.0 and 31.2, respectively. One week after admission, the PNI was 30.7 in the NYT group and 24.4 in non-NYT group. PNI was significantly (p = 0.032) increased in the NYT group (+13.6%) than in the non-NYT group (-22.0%). The Japanese Kampo medicine NYT might be useful for treating patients with severe COVID-19 in ICU. This study was conducted in a small number of cases, and further large clinical trials are necessary.
- Published
- 2021
15. Uncovering the Role of Gut Microbiota in Amino Acid Metabolic Disturbances in Heart Failure Through Metagenomic Analysis
- Author
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Tomohiro Hayashi, Tomoya Yamashita, Tomoya Takahashi, Tokiko Tabata, Hikaru Watanabe, Yasuhiro Gotoh, Masakazu Shinohara, Kenjiro Kami, Hidekazu Tanaka, Kensuke Matsumoto, Tetsuya Hayashi, Takuji Yamada, and Ken-ichi Hirata
- Subjects
medicine.medical_specialty ,amino acid (AA) ,heart failure ,Cardiovascular Medicine ,Gut flora ,chemistry.chemical_compound ,Biosynthesis ,Internal medicine ,medicine ,Prevotella ,Diseases of the circulatory (Cardiovascular) system ,Eubacterium ,Histidine ,Feces ,Original Research ,chemistry.chemical_classification ,biology ,gut microbiota ,metagenomic analysis ,Metabolism ,biology.organism_classification ,Amino acid ,Endocrinology ,chemistry ,RC666-701 ,Cardiology and Cardiovascular Medicine ,metabolism - Abstract
Aims: Circulating amino acid (AA) abnormalities serve as predictors of adverse outcomes in patients with heart failure (HF). However, the role of the gut microbiota in AA disturbances remains unknown. Thus, we investigated gut microbial functions and their associations with AA metabolic alterations in patients with HF.Methods and Results: We performed whole-genome shotgun sequencing of fecal samples and mass spectrometry-based profiling of AAs in patients with compensated HF. Plasma levels of total essential AAs (EAAs) and histidine were significantly lower in patients with HF than in control subjects. HF patients also displayed increased and decreased abundance of gut microbial genes involved in the degradation and biosynthesis, respectively, of EAAs, including branched-chain AAs (BCAAs) and histidine. Importantly, a significant positive correlation was observed between the abundance of microbial genes involved in BCAA biosynthesis and plasma BCAA levels in patients with HF, but not in controls. Moreover, network analysis revealed that the depletion of Eubacterium and Prevotella, which harbor genes for BCAA and histidine biosynthesis, contributed to decreased abundance of microbial genes involved in the biosynthesis of those EAAs in patients with HF.Conclusions: The present study demonstrated the relationship between gut microbiota and AA metabolic disturbances in patients with HF.
- Published
- 2021
16. Bacteroides spp. promotes branched-chain amino acid catabolism in brown fat and inhibits obesity
- Author
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Ken-ichi Hirata, Yushi Hirota, Wataru Ogawa, Akihiko Kondo, Yoshiharu Shimomura, Masayuki Saito, Seiichi Kitahama, Kengo Sasaki, Masakazu Shinohara, Tatsunori Osone, Shingo Kajimura, Takeshi Yoneshiro, Takuji Yamada, Tetsuya Hosooka, Yoshihiro Saito, Yasuyuki Kitaura, Takuo Emoto, Yuko Okamatsu-Ogura, Takeshi Inagaki, Tomohiro Suzuki, Genki Ozawa, Daisuke Sasaki, Naofumi Yoshida, and Tomoya Yamashita
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Multidisciplinary ,Computer systems organization ,Catabolism ,Science ,Energy systems ,Branched-chain amino acid ,Bacteroides dorei ,Energy engineering ,Metabolism ,Biology ,Gut flora ,biology.organism_classification ,Article ,Amino acid ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Internal medicine ,Brown adipose tissue ,medicine ,Bacteroides - Abstract
Summary The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with Bacteroides dorei and Bacteroides vulgatus exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that Bacteroides probiotics could be used for treating obesity., Graphical abstract, Highlights • Gut microbiota regulated BAT BCAA catabolism • Bacteroides promoted BAT BCAA catabolism and inhibited obesity • Bacteroides suppressed BAT inflammation that contributed to BAT BCAA catabolic defect, Computer systems organization; Energy engineering; Energy systems
- Published
- 2021
17. Giant Coronary Arterial Aneurysm of the Proximal Left Anterior Descending Artery as the Cause of Wide Splitting of the Second Heart Sound
- Author
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Tomomi Akita, Tsumugi Oki, Akira Nagasawa, Tomoya Yamashita, Haruhi Yamada, Tatsuya Nishii, Ken-ichi Hirata, Shumpei Mori, and Yutaka Okita
- Subjects
Adult ,medicine.medical_specialty ,second heart sound ,Cardiac computed tomography ,phonocardiography ,Case Report ,Aorta, Thoracic ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Abnormal heart sounds ,Internal medicine ,medicine.artery ,Internal Medicine ,medicine ,Thoracic aorta ,Proximal left anterior descending artery ,Humans ,Sound (medical instrument) ,medicine.diagnostic_test ,business.industry ,Coronary Aneurysm ,Arterial aneurysm ,computed tomography ,General Medicine ,Auscultation ,Coronary Vessels ,Heart Sounds ,Echocardiography ,Heart sounds ,Cardiology ,030211 gastroenterology & hepatology ,Female ,business ,coronary arterial aneurysm - Abstract
Even in modern clinical cardiology, basic auscultation skill is not obsolete and is still important because it can always provide a clue to an underlying pathophysiology. We demonstrate an unusual mechanism of pathological wide splitting of the second heart sound due to external compression of the pulmonary trunk in a patient with a giant coronary arterial aneurysm of the proximal left anterior descending artery. Echocardiography, when combined with a three-dimensional anatomical analysis with cardiac computed tomography, was useful for elucidating the mechanism of the abnormal heart sounds.
- Published
- 2017
18. Impact of CD14++CD16+ monocytes on plaque vulnerability in diabetic and non-diabetic patients with asymptomatic coronary artery disease: a cross-sectional study
- Author
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Naofumi Yoshida, Wataru Ogawa, Takuo Emoto, Taiji Mizoguchi, Yushi Hirota, Tomoya Yamashita, Ken-ichi Hirata, Hilman Zulkifli Amin, Naoto Sasaki, Kazuhiko Sakaguchi, Hachidai Takahashi, Hiroyuki Yamamoto, Hiromasa Otake, Toshiro Shinke, Daisuke Terashita, Tomohiro Hayashi, and Masaru Kuroda
- Subjects
Thin-cap fibroatheroma ,medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,Endocrinology, Diabetes and Metabolism ,CD14 ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Asymptomatic ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,medicine ,CD14++CD16+ monocytes ,Glucose fluctuations ,Glycemic ,Angiology ,business.industry ,Monocyte ,medicine.disease ,Coronary plaque vulnerability ,medicine.anatomical_structure ,lcsh:RC666-701 ,CD14(++)CD16(+) monocytes ,Cardiology ,Biomarker (medicine) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Previously, we have reported that daily glucose fluctuations could affect coronary plaque vulnerability, but the underlying mechanisms remained unclear. This study sought to investigate the impact of CD14++CD16+ monocytes on plaque vulnerability, as assessed by virtual histology intravascular ultrasound (VH-IVUS), as well as their relationship to fluctuating glucose levels in patients with asymptomatic coronary artery disease (CAD). Methods Fifty-one patients with asymptomatic CAD, who were undergoing lipid-lowering therapy and underwent VH-IVUS evaluation for angiographically mild to moderate lesions, were enrolled in the study. Standard VH-IVUS parameters, including the percentage volume of the necrotic core (%NC) within the plaque and the presence of a virtual histology thin-cap fibroatheroma (VH-TCFA), were then evaluated. Additionally, monocyte subsets were assessed by flow cytometry, and daily glucose fluctuations were analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results Among 82 plaques from 22 diabetes mellitus (DM) patients and 29 non-DM patients, 15 VH-TCFAs were identified. CD14++CD16+ monocyte counts significantly correlated with both %NC and the presence of VH-TCFA (%NC: r = 0.339, p = 0.002; VH-TCFA: p = 0.003). Multivariate logistic regression analysis revealed that CD14++CD16+ monocyte counts were independently associated with VH-TCFA (odds ratio = 1.029, p = 0.004). Furthermore, CD14++CD16+ monocyte counts were significantly correlated with the MAGE score in the non-DM patients (r = 0.544, p = 0.005). Conclusions CD14++CD16+ monocyte levels are associated with coronary plaque vulnerability and can serve as a biomarker for VH-TCFA in patients with CAD undergoing lipid-lowering therapy. In patients without DM, glucose fluctuations may alter the balance of monocyte subsets. Trial registration UMIN Registry number: UMIN000021228
- Published
- 2017
19. Intestinal Immunity and Gut Microbiota in Atherogenesis
- Author
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Tomoya Yamashita
- Subjects
0301 basic medicine ,Vitamin ,Intestinal immunity ,Gut–brain axis ,TMAO ,Review ,Gut microbiota ,030204 cardiovascular system & hematology ,Gut flora ,digestive system ,Coronary artery disease ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oral administration ,Internal Medicine ,Animals ,Humans ,Medicine ,biology ,business.industry ,Biochemistry (medical) ,Atherosclerosis ,biology.organism_classification ,medicine.disease ,Gastrointestinal Microbiome ,Review article ,Intestines ,030104 developmental biology ,chemistry ,Tolerogenic dendritic cell ,Immunology ,biology.protein ,Antibody ,Cardiology and Cardiovascular Medicine ,business ,Regulatory T cell - Abstract
Atherosclerosis is a chronic inflammatory disease. Interventions targeting the inflammatory process could provide new strategies for preventing atherosclerotic cardiovascular diseases (CVD). Previously, we have reported that oral administration of anti-CD3 antibodies, or active vitamin D3, reduced atherosclerosis in mice via recruiting regulatory T cells and tolerogenic dendritic cells to the gut-associated lymphoid tissues. From this, it is reasonable to propose that the intestine could be a novel therapeutic target for prevention of atherosclerotic CVD. Recently, the association between cardio-metabolic diseases and gut microbiota has attracted increased attention. Gut microbiota, reported to be highly associated with intestinal immunity and metabolism, were shown to aggravate CVD by contributing to the production of trimethylamine-N-oxide (TMAO), a pro-atherogenic compound. We have also previously investigated the relationship between patient susceptibility to coronary artery disease (CAD) and gut microbiota. We found that the order Lactobacillales was significantly increased and the phylum Bacteroidetes was decreased in CAD patients compared with control patients. In this review article, we discuss the evidence for the relationship between the gut microbiota and cardio-metabolic diseases, and consider the gut microbiota as new potential diagnostic and therapeutic tool for treating CVD.
- Published
- 2017
20. P5508Impact of CD14++CD16+ monocytes on coronary plaque vulnerability assessed by optical coherence tomography in coronary artery disease patients
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Yoichiro Sugizaki, Hiroyuki Yamamoto, Naofumi Yoshida, Yoshiro Tsukiyama, Kenichi Yanaka, Takayoshi Toba, Akira Nagasawa, Tomoya Yamashita, Hiromasa Otake, Hiroyuki Onishi, Hiroyuki Kawamori, Yuichiro Nagano, Ryo Takeshige, T. Shinke, and K Hirata
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Vulnerability ,medicine.disease ,Coronary artery disease ,Optical coherence tomography ,Internal medicine ,Coronary plaque ,medicine ,Cardiology ,Cd14 cd16 monocytes ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Diabetes mellitus has been known as an important factor of coronary artery disease (CAD) progression despite of widespread with lipid-lowering therapy. Although we have reported that large glucose fluctuation is associated with the development of cardiovascular disease in both diabetes mellitus (DM) and non-DM patients, the underlying mechanisms remain unclear. Monocytes play a key role for atherosclerotic plaque formation. Monocytes in human peripheral blood are divided into three subsets: CD14++CD16− monocytes, CD14++CD16+ monocytes, and CD14+CD16++ monocytes. The CD14++CD16+ monocyte subset has recently received attention because it is reported to be associated with future cardiovascular events such as acute myocardial infarction. However, their impact on coronary plaque vulnerability in coronary artery disease (CAD) patients with or without DM remains unclear. Purpose The aim of this study was to investigate the impact of CD14++CD16+ monocyte levels on coronary plaque vulnerability and glucose fluctuation in stable CAD patients with well-regulated lipid levels. Methods This prospective observational study included 50 consecutive patients with CAD (DM [n=22], Non-DM [n=28]), receiving lipid-lowering therapy and undergoing coronary angiography and optical coherence tomography (OCT). Patients were divided into 3 tertiles according to the CD14++CD16+ monocyte percentages assessed by flow cytometry. Standard OCT parameters including lipid arc, lipid length, fibrous cap thickness (FCT) on lipid rich plaque, were assessed for 97 angiographically intermediate lesions (diameter stenosis: 30–70%). The presence of thin-cap fibroatheroma (TCFA), defined as a thin fibrous cap (90°), was also assessed. Daily glucose fluctuation assessed by using continuous glucose monitoring system was analyzed by measuring the mean amplitude of glycemic excursion (MAGE). Results CD14++CD16+ monocytes negatively correlated with FCT on lipid rich plaque (r=0.508, p Conclusions CD14++CD16+ monocytes were associated with coronary plaque vulnerability in CAD patients with well-regulated lipid levels both in DM and non-DM patients. Cross-talk between glucose fluctuation and CD14++CD16+ monocytes may enhance plaque vulnerability, particularly in non-DM patients. CD14++CD16+ monocytes could be a possible therapeutic target for coronary plaque stabilization.
- Published
- 2019
21. Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease
- Author
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Takuya Matsumoto, Yushi Hirota, Kazuyuki Kasahara, Wataru Ogawa, Naoto Sasaki, Tomohiro Hayashi, Anna So, Takuo Emoto, Ken-ichi Hirata, Taiji Mizoguchi, Keiko Yodoi, and Tomoya Yamashita
- Subjects
DNA, Bacterial ,Male ,0301 basic medicine ,medicine.medical_specialty ,Coronary Artery Disease ,Type 2 diabetes ,030204 cardiovascular system & hematology ,Gut flora ,digestive system ,Gastroenterology ,Coronary artery disease ,Feces ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Humans ,Obesity ,Prospective cohort study ,Aged ,biology ,Bacteroidetes ,business.industry ,Biochemistry (medical) ,Case-control study ,Middle Aged ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Female ,Original Article ,Enterotype ,Cardiology and Cardiovascular Medicine ,business ,Polymorphism, Restriction Fragment Length - Abstract
AIM: Recent studies have suggested that metabolic disorders such as obesity and type 2 diabetes are associated with gut microbiota. The association between atherosclerosis and gut microbiota has also been attracting increased attention. Our aim was to specify a characteristic trend of gut microbiota in coronary artery disease (CAD). METHODS: This study included 39 CAD patients, 30 age- and sex-matched no-CAD controls (Ctrls) with coronary risk factors and 50 healthy volunteers (HVs) without coronary risk factors. Bacterial DNA was extracted from their fecal samples and analyzed by terminal restriction fragment length polymorphism. RESULTS: A characteristic change of gut microbiota was observed in CAD patients, where the order Lactobacillales was increased (CAD, Ctrl vs. HV; 13.6% ± 12.0%, 6.2% ± 7.7% vs. 4.1% ± 5.9%; p < 0.001) and the phylum Bacteroidetes (Bacteroides + Prevotella) was decreased (CAD, Ctrl vs. HV; 35.5% ± 11.6%, 43.9% ± 11.2% vs. 47.4% ± 11.5%; p < 0.001). The CAD group was over-represented in enterotype “others” (III), compared with the Ctrl or HV group (p < 0.001, chi-squared test), although we could not deny the possibility that some drugs affect the gut flora types. CONCLUSIONS: Although this study had some limitations, we demonstrated that the incidence of CAD was linked with an alteration of gut microbiota. A prospective study is desired to clarify a causal relationship between CAD and gut microbiota.
- Published
- 2016
22. The impact of antibiotics on the metabolic status of obese adults without bacterial infection: a systematic review and meta-analysis
- Author
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Yasushi Tsujimoto, Shunsuke Taito, Yoshihiro Saito, Masahiro Banno, Yuki Kataoka, Ken-ichi Hirata, Tomoya Yamashita, and Naofumi Yoshida
- Subjects
medicine.medical_specialty ,biology ,medicine.drug_class ,business.industry ,Antibiotics ,General Medicine ,Gut flora ,Overweight ,biology.organism_classification ,medicine.disease ,Placebo ,Gastroenterology ,Obesity ,antibiotics ,meta-analysis ,Diarrhea ,Insulin resistance ,systematic review ,Internal medicine ,medicine ,Original Article ,medicine.symptom ,Adverse effect ,business - Abstract
BACKGROUND: The gut microbiota is involved in the pathophysiology of obesity. It is known that oral antibiotics manipulate the gut microbiota; however, the impact on host metabolism of obese adults without bacterial infection has not been systematically summarized. METHODS: We searched for randomized, placebo-controlled trials that investigated the effects of oral antibiotics on the metabolic status in obese adults via Medline, EMBASE, and the Cochrane Library. Primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR), body weight, and rate of diarrhea. Additional outcomes included fasting plasma glucose (FPG), plasma glucagon-like peptide-1 (GLP-1), waist circumference, fecal short-chain fatty acid (SCFA) levels, and all adverse events. We assessed the certainty of evidence based on Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: Among 1,762 articles screened, four studies were eligible for quantitative analysis, two of which were applied to meta-analysis. Oral antibiotics had low influence on HOMA-IR [mean difference (MD) 0.09 (95% CI: −0.96 to 1.13)], body weight [MD 4.1 kg (95% CI: −23.77 to 31.97)], FPG [MD −0.12 mmol/L (95% CI: −0.47 to 0.23)], and GLP-1 [MD 0.20 pmol/L (95% CI: −2.36 to 2.76)] compared to placebo. Antibiotics treatment altered fecal acetate and butyrate levels, but resulted in little difference in propionate levels [MD −13.60 µmol/g (95% CI: −22.43 to −4.77), MD −7.60 µmol/g (−10.97 to −4.23), MD −1.10 µmol/g (95% CI: −4.18 to 1.98), respectively]. Several adverse events, such as sun sensitivity and gastrointestinal discomfort, were reported following antibiotics treatment, but no diarrhea. The certainty of evidence for most outcomes was very low to low, except for fecal SCFAs. CONCLUSIONS: Our results indicate that oral antibiotics treatment is insufficient to ameliorate metabolic parameters in obese adults, suggesting that oral antibiotics treatment may not qualify as a therapeutic approach for obesity.
- Published
- 2020
23. [113th Scientific Meeting of the Japanese Society of Internal Medicine: Symposium: Gut Microbiota and Cardiovascular Disease]
- Author
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Ken-ichi, Hirata and Tomoya, Yamashita
- Subjects
Japan ,Cardiovascular Diseases ,Internal Medicine ,Animals ,Humans ,Societies, Medical ,Gastrointestinal Microbiome - Published
- 2018
24. A case of fatal heart and liver failure accompanied by thyroid storm treated with prompt plasma exchange
- Author
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Tomofumi Takaya, Naofumi Yoshida, Hiroyuki Sano, Jun Ito, Tomoya Yamashita, Hidenori Fukuoka, Feibi Zeng, Makiko Suto, Tatsuro Ito, Yu Hatani, and Ken-ichi Hirata
- Subjects
Liver injury ,medicine.medical_specialty ,endocrine system ,Ejection fraction ,endocrine system diseases ,business.industry ,Thyroid ,030204 cardiovascular system & hematology ,medicine.disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Heart failure ,Internal medicine ,medicine ,Cardiology ,Thyroid storm ,030211 gastroenterology & hepatology ,Liver function ,Cardiology and Cardiovascular Medicine ,Complication ,business ,Hormone - Abstract
A 36-year-old man with a history of Graves' disease was admitted complaining of dyspnea. He was diagnosed with acute heart failure and severe liver dysfunction accompanied by thyroid storm. Left ventricular ejection fraction was 19%, and liver enzyme levels were markedly elevated followed with coagulation disorders. In addition to the conventional therapy, we performed plasma exchange emergently. Thyroid hormone levels promptly normalized, then his clinical condition improved. Finally, his cardiac and liver function almost normalized from a fatal condition without serious complications. Hyperthyroidism can cause myocardial and liver injury, hence thyroid hormone removal in acute phase is important. Prompt plasma exchange is effective in the acute phase for heart and liver failure accompanied by thyroid storm. Learning objective: Thyroid storm is a life-threatening condition. Prompt reduction of serum free thyroid hormone is important in fatal conditions. Because plasma exchange (PE) can decrease serum thyroid hormone and improve critical condition, PE should be conducted emergently. In the present case, we promptly performed PE for the patient with potentially fatal heart and liver failure. We could treat him without any complication. We wish to emphasize the importance of prompt PE in acute phase of thyroid storm.>
- Published
- 2017
25. Bicuspid Aortic Valve-Associated Aortic Dilatation ― What Is the Mechanism of Bicuspid Aortopathy? ―
- Author
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Tokiko Tabata, Ken-ichi Hirata, Tomoya Yamashita, and Tomohiro Hayashi
- Subjects
Aortic dilatation ,medicine.medical_specialty ,Aorta ,business.industry ,Mechanism (biology) ,Heart Valve Diseases ,General Medicine ,030204 cardiovascular system & hematology ,medicine.disease ,Dilatation ,03 medical and health sciences ,0302 clinical medicine ,Bicuspid aortic valve ,Text mining ,Bicuspid Aortic Valve Disease ,Aortic Valve ,Internal medicine ,medicine.artery ,medicine ,Cardiology ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Proto-Oncogene Proteins c-akt - Published
- 2018
26. Very late-onset reversible cardiomyopathy in patients with chronic GvHD
- Author
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Yoshio Katayama, Fumi Kawakami, Kanako Wakahashi, Hidekazu Tanaka, Shinichi Ishii, Tomoya Yamashita, Yuko Kawano, Kentaro Minagawa, Toshimitsu Matsui, Hiroki Kawano, Tomoo Itoh, Tomohide Suzuki, Akiko Sada, Akiyasu Baba, and Ken-ichi Hirata
- Subjects
Transplantation ,medicine.medical_specialty ,Myeloid ,business.industry ,Cardiomyopathy ,MEDLINE ,Late onset ,Hematology ,medicine.disease ,Surgery ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,medicine ,Peripheral Blood Stem Cell Transplantation ,Chronic gvhd ,In patient ,business - Published
- 2015
27. Steroid-induced Paraparesis: Spinal Epidural Lipomatosis Complicated by a Wedge Deformity of the Middle Thoracic Vertebrae
- Author
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Kenji Ohzono, Tetsuo Ohwada, Tomoya Yamashita, Hironobu Sakaura, and Toshitada Miwa
- Subjects
Epidural Space ,medicine.medical_specialty ,Radiography ,Lipomatosis ,medicine.medical_treatment ,Thoracic Vertebrae ,Steroid ,Paraparesis ,Internal Medicine ,Deformity ,medicine ,Humans ,medicine.diagnostic_test ,business.industry ,Vertebral compression fracture ,Magnetic resonance imaging ,General Medicine ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Thoracic vertebrae ,Spinal Fractures ,Female ,Steroids ,medicine.symptom ,business ,Complication - Abstract
Steroid therapy is commonly prescribed, although a variety of complications have been reported. Among such complications, spinal epidural lipomatosis is rare and difficult to diagnose before paraparesis occurs. The purpose of this report is to present a rare but catastrophic complication of steroid therapy. A 64-year-old woman undergoing long-term steroid therapy suffered from an osteoporotic vertebral compression fracture and was unable to walk due to paraparesis. Magnetic resonance imaging (MRI) demonstrated a D7 compression fracture and stored epidural adipose tissue between D5 and D8. After surgery, the patient was able to walk with double canes. This case indicates that long-term steroid use has the potential to induce paraparesis.
- Published
- 2013
28. Isolated Primary Cardiac Sarcoidosis Presenting as Acute Heart Failure
- Author
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Yoichiro Sugizaki, Ken-ichi Hirata, Tomoya Yamashita, Hiroya Kawai, Junichi Imanishi, Hidekazu Tanaka, Toshiro Shinke, Akihide Konishi, and Tatsuro Ishida
- Subjects
Male ,medicine.medical_specialty ,Myocarditis ,Sarcoidosis ,Prednisolone ,Inflammation ,Cardiac sarcoidosis ,Risk Assessment ,Diagnosis, Differential ,Ventricular Dysfunction, Left ,Internal medicine ,Biopsy ,Internal Medicine ,medicine ,Humans ,Heart Failure ,Ejection fraction ,medicine.diagnostic_test ,business.industry ,Biopsy, Needle ,Epithelioid cell granuloma ,General Medicine ,medicine.disease ,Immunohistochemistry ,Dyspnea ,Treatment Outcome ,Echocardiography ,Positron-Emission Tomography ,Heart failure ,Acute Disease ,Cardiology ,Radiography, Thoracic ,medicine.symptom ,Cardiomyopathies ,business - Abstract
A 65-year-old man was referred to our hospital due to an acute onset of dyspnea and persistent fever. Echocardiography revealed an ejection fraction (EF) of 25% with diffuse severe left ventricular (LV) dysfunction. 18F-fluorodeoxy glucose-positron emission tomography imaging showed significantly increased uptake by the LV and right ventricular walls, indicating active inflammation. The histologic findings of the endomyocardial biopsy specimens indicated the presence of epithelioid cell granuloma. The final diagnosis was thus cardiac sarcoidosis with acute inflammation. Five-months after the initiation of steroid therapy, echocardiography showed an EF of 50%. This is a rare case in which acute inflammation led to acute heart failure mimicking acute myocarditis.
- Published
- 2013
29. Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis
- Author
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Takeshi Tanoue, Taiji Mizoguchi, Tomohiro Hayashi, Takuya Matsumoto, Kenya Honda, Takuo Emoto, Kazuyuki Kasahara, Naoto Sasaki, Keiko Yodoi, Tomoya Yamashita, Ken-ichi Hirata, Koji Atarashi, and Naoki Kitano
- Subjects
0301 basic medicine ,Gut flora ,Systemic inflammation ,Biochemistry ,chemistry.chemical_compound ,Mice ,Endocrinology ,Homeostasis ,Cholesterol 7-alpha-Hydroxylase ,Research Articles ,Bile acid ,biology ,Chemistry ,macrophages ,Cholesterol ,lipids (amino acids, peptides, and proteins) ,nuclear receptors/farnesoid X receptor ,medicine.symptom ,medicine.medical_specialty ,medicine.drug_class ,Inflammation ,cholesterol/metabolism ,QD415-436 ,digestive system ,03 medical and health sciences ,Apolipoproteins E ,Ileum ,Internal medicine ,medicine ,Animals ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,Liver X receptor ,Bacteria ,gut microbiota ,bile acid metabolism ,Lipid metabolism ,Cell Biology ,Fibroblast growth factor receptor 4 ,biology.organism_classification ,Atherosclerosis ,Lipid Metabolism ,Diet ,Gastrointestinal Microbiome ,Fibroblast Growth Factors ,Disease Models, Animal ,030104 developmental biology - Abstract
The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free (GF) or conventionally raised (Conv) Apolipoprotein E deficient (ApoE(-/-)) mice were fed chow diet and sacrificed at twenty weeks of age. We found lack of gut microbiota in ApoE(-/-) mice caused a significant increase in the plasma and hepatic cholesterol levels compared to ConvR ApoE(-/-) mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the entero-hepatic fibroblast growth factor 15 (FGF15) - fibroblast growth factor receptor 4 (FGFR4) axis, and reduction of cholesterol 7α-hydroxylase (CYP7A1) and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared to Conv ApoE(-/-) mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice.
- Published
- 2016
30. Expression of Endothelial Lipase Correlates with the Size of Neointima in a Murine Model of Vascular Remodeling
- Author
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Tatsuro Ishida, Masakazu Shinohara, Li Sun, Tomoyuki Yasuda, Takeaki Okada, Ken-ichi Hirata, Tomoya Yamashita, Yoshiyuki Rikitake, Ryuji Toh, and Tetsuya Hara
- Subjects
Endothelial lipase ,Neointima ,medicine.medical_specialty ,Vascular smooth muscle ,Endothelium ,Carotid Artery, Common ,Lipoproteins ,Myocytes, Smooth Muscle ,Inflammation ,Gene Expression Regulation, Enzymologic ,Mice ,Cell Movement ,Internal medicine ,Cell Adhesion ,Internal Medicine ,medicine ,Animals ,Humans ,Myocyte ,Extracellular Signal-Regulated MAP Kinases ,Cell Proliferation ,Mice, Knockout ,Dose-Response Relationship, Drug ,Cell adhesion molecule ,Chemistry ,Angiotensin II ,Biochemistry (medical) ,Cell migration ,Lipase ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,Endothelium, Vascular ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
Aim Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice. Methods Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells. Results Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin II-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth. Conclusion EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration.
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- 2012
31. Orally Administered Eicosapentaenoic Acid Induces Rapid Regression of Atherosclerosis Via Modulating the Phenotype of Dendritic Cells in LDL Receptor-Deficient Mice
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Masafumi Takeda, Kazuyuki Kasahara, Naoto Sasaki, Mitsuhiro Yokoyama, Yoshiyuki Rikitake, Masakazu Shinohara, Kenji Nakajima, Tomoya Yamashita, Tatsuro Ishida, Ken-ichi Hirata, and Tomoyuki Kita
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Male ,medicine.medical_specialty ,Normal diet ,T-Lymphocytes ,T cell ,Administration, Oral ,CD11c ,Biology ,Mice ,Immune system ,Internal medicine ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,RNA, Messenger ,CD86 ,Dendritic Cells ,Atherosclerosis ,Eicosapentaenoic acid ,Phenotype ,medicine.anatomical_structure ,Endocrinology ,Eicosapentaenoic Acid ,Receptors, LDL ,LDL receptor ,Immunology ,Cytokines ,Cardiology and Cardiovascular Medicine ,CD80 - Abstract
Objective— Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. Methods and Results— LDL-receptor–deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (−22.7%, P + T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c + CD80 − CD86 − ), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4 + T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. Conclusion— In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence.
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- 2011
32. Foxp3+ Regulatory T Cells Regulates Immunoinflammatory Responses and Prevents Atherosclerosis in Hypercholesterolemic Mice
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Tomohiro Hayashi, Naofumi Yoshida, Kazuyuki Kasahara, Ken-ichi Hirata, Hilman Zulkifli Amin, Takuo Emoto, Taiji Mizoguchi, Naoto Sasaki, Yoshiyuki Rikitake, and Tomoya Yamashita
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03 medical and health sciences ,0302 clinical medicine ,business.industry ,Immunology ,Internal Medicine ,Medicine ,FOXP3 ,030212 general & internal medicine ,General Medicine ,030204 cardiovascular system & hematology ,Cardiology and Cardiovascular Medicine ,business - Published
- 2018
33. Beneficial Effects of Exogenous Tetrahydrobiopterin on Left Ventricular Remodeling After Myocardial Infarction in Rats The Possible Role of Oxidative Stress Caused by Uncoupled Endothelial Nitric Oxide Synthase
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Mitsuhiro Yokoyama, Masakazu Shinohara, Ken-ichi Hirata, Naoto Sasaki, Tomoya Masano, Tomoya Yamashita, Seinosuke Kawashima, Ryuji Toh, Seimi Satomi-Kobayashi, Tomofumi Takaya, Masafumi Takeda, and Hideto Tawa
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chemistry.chemical_classification ,Reactive oxygen species ,medicine.medical_specialty ,biology ,Chemistry ,Superoxide ,General Medicine ,Tetrahydrobiopterin ,medicine.disease ,biology.organism_classification ,medicine.disease_cause ,Nitric oxide synthase ,chemistry.chemical_compound ,Endocrinology ,Enos ,Dihydrobiopterin ,Internal medicine ,medicine ,biology.protein ,Cardiology and Cardiovascular Medicine ,Ventricular remodeling ,Oxidative stress ,medicine.drug - Abstract
Background Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. Methods and Results Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function was preserved compared with the control MI rats. Conclusions The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function. (Circ J 2008; 72: 1512 - 1519)
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- 2008
34. Central Role of Calcium-Dependent Tyrosine Kinase PYK2 in Endothelial Nitric Oxide Synthase–Mediated Angiogenic Response and Vascular Function
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Kento Tateishi, Shoken Honshou, Shinji Takai, Hiroaki Matsubara, Akihiro Matsui, Tatsuya Kurihara, Katsuya Amano, Yasushi Adachi, Mizuo Miyazaki, Tetsuro Kusaba, Shinsaku Matsunaga, Tomoya Yamashita, Seinosuke Kawashima, Tomosaburo Takahashi, Denan Jin, Tetsuya Tatsumi, Mitsuhiko Okigaki, Asako Katsume, and Satoaki Matoba
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Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Angiogenesis ,Neovascularization, Physiologic ,Biology ,Vascular endothelial growth inhibitor ,Mice ,chemistry.chemical_compound ,Ischemia ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Phosphorylation ,S1PR1 ,Mice, Knockout ,Analysis of Variance ,Akt/PKB signaling pathway ,Heart ,Hindlimb ,Cell biology ,Enzyme Activation ,Oncogene Protein v-akt ,Vasodilation ,Vascular endothelial growth factor ,Vascular endothelial growth factor B ,Vascular endothelial growth factor A ,Focal Adhesion Kinase 2 ,Endocrinology ,chemistry ,Vascular endothelial growth factor C ,Calcium ,Cardiology and Cardiovascular Medicine ,Signal Transduction - Abstract
Background— The involvement of Ca 2+ -dependent tyrosine kinase PYK2 in the Akt/endothelial NO synthase pathway remains to be determined. Methods and Results— Blood flow recovery and neovessel formation after hind-limb ischemia were impaired in PYK2 −/− mice with reduced mobilization of endothelial progenitors. Vascular endothelial growth factor (VEGF)–mediated cytoplasmic Ca 2+ mobilization and Ca 2+ -independent Akt activation were markedly decreased in the PYK2-deficient aortic endothelial cells, whereas the Ca 2+ -independent AMP-activated protein kinase/protein kinase-A pathway that phosphorylates endothelial NO synthase was not impaired. Acetylcholine-mediated aortic vasorelaxation and cGMP production were significantly decreased. Vascular endothelial growth factor–dependent migration, tube formation, and actin cytoskeletal reorganization associated with Rac1 activation were inhibited in PYK2-deficient endothelial cells. PI3-kinase is associated with vascular endothelial growth factor–induced PYK2/Src complex, and inhibition of Src blocked Akt activation. The vascular endothelial growth factor–mediated Src association with PLCγ1 and phosphorylation of 783 Tyr-PLCγ1 also were abolished by PYK2 deficiency. Conclusion— These findings demonstrate that PYK2 is closely involved in receptor- or ischemia-activated signaling events via Src/PLCγ1 and Src/PI3-kinase/Akt pathways, leading to endothelial NO synthase phosphorylation, and thus modulates endothelial NO synthase–mediated vasoactive function and angiogenic response.
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- 2007
35. A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression
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Masami Goto, Toshio Hayashi, Masakazu Shinohara, Seinosuke Kawashima, Nobutaka Inoue, Naoto Sasaki, Toyotaka Yada, Keith M. Channon, Nicholas J. Alp, Tomofumi Takaya, Mitsuhiro Yokoyama, Ken-ichi Hirata, Akiko Fukatsu, and Tomoya Yamashita
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Apolipoprotein E ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Endothelium ,chemistry.chemical_element ,Ascorbic Acid ,Sensitivity and Specificity ,Oxygen ,Antioxidants ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,Superoxides ,Enos ,Internal medicine ,medicine ,Animals ,GTP Cyclohydrolase ,Probability ,chemistry.chemical_classification ,Analysis of Variance ,Reactive oxygen species ,Vitamin C ,biology ,Superoxide ,Tetrahydrobiopterin ,Atherosclerosis ,biology.organism_classification ,Biopterin ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Female ,Endothelium, Vascular ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Objective— When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E–deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. Methods and Results— We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production. Conclusion— In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS.
- Published
- 2007
36. CIRCULATING INTERMEDIATE CD14++CD16+ MONOCYTES ARE INCREASED IN PATIENTS WITH ATRIAL FIBRILLATION AND REFLECT FUNCTIONAL REMODELING OF LEFT ATRIUM
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Tomoyuki Nakanishi, Takuo Emoto, Ken-ichi Hirata, Asumi Takei, Hirotoshi Ichibori, Atsushi Suzuki, Akinori Matsumoto, Ryudo Fujiwara, Koji Fukuzawa, Nobutaka Inoue, Akihiro Yoshida, Naoto Sasaki, Hiroki Konishi, Tomoya Yamashita, and Soichiro Yamashita
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medicine.medical_specialty ,business.industry ,CD14 ,Left atrium ,Atrial fibrillation ,CD16 ,medicine.disease ,Pathophysiology ,Clinical study ,medicine.anatomical_structure ,Internal medicine ,Cardiology ,Medicine ,Cd14 cd16 monocytes ,In patient ,business ,Cardiology and Cardiovascular Medicine - Abstract
Recent large clinical study demonstrated association of intermediate CD14++CD16+monocytes (IM) with cardiovascular events. We investigated the possible role of IM in pathophysiology of atrial fibrillation (AF). This case-control study included 30 AF patients (17 paroxysmal and 13 persistent AF
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- 2015
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37. Foxp3+ regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice
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Takuo Emoto, Yoshihiro Sasaki, Kazuyuki Kasahara, Naoto Sasaki, Takuya Matsumoto, Taiji Mizoguchi, Tomoyuki Kita, Tim Sparwasser, Keiko Yodoi, Ken-ichi Hirata, and Tomoya Yamashita
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Interleukin 2 ,Male ,Pathology ,medicine.medical_specialty ,chemical and pharmacologic phenomena ,Inflammation ,Endogeny ,T-Lymphocytes, Regulatory ,Aortic aneurysm ,Mice ,Internal Medicine ,medicine ,Animals ,Aorta, Abdominal ,Immunity, Cellular ,business.industry ,Angiotensin II ,FOXP3 ,hemic and immune systems ,Forkhead Transcription Factors ,medicine.disease ,Flow Cytometry ,Immunohistochemistry ,Abdominal aortic aneurysm ,Mice, Inbred C57BL ,Disease Models, Animal ,Immunology ,cardiovascular system ,medicine.symptom ,business ,medicine.drug ,Aortic Aneurysm, Abdominal - Abstract
Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3 + Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3 + Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E–deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II–infused mice received interleukin-2/anti–interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II–infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3 + Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3 + Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3 + Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3 + Tregs against AAA. Our findings suggest that Foxp3 + Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.
- Published
- 2015
38. An X-Ray Diffraction Study on Mouse Cardiac Cross-Bridge Function In Vivo: Effects of Adrenergic β-Stimulation
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Ryuji Toh, Masakazu Shinohara, Seinosuke Kawashima, Tomofumi Takaya, Shigeru Masuda, Naoto Yagi, Mitsuhiro Yokoyama, and Tomoya Yamashita
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Male ,medicine.medical_specialty ,Protein Conformation ,Diastole ,Biophysics ,Myosins ,Biology ,Sarcomere ,Contractility ,Mice ,QRS complex ,Lattice constant ,Nuclear magnetic resonance ,X-Ray Diffraction ,Dobutamine ,Internal medicine ,medicine ,Animals ,Muscle and Contractility ,Systole ,Cardiac muscle ,Heart ,Adrenergic beta-Agonists ,Myocardial Contraction ,Actins ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,medicine.drug - Abstract
To investigate how beta-stimulation affects the contractility of cardiac muscle, x-ray diffraction from cardiac muscle in the left ventricular free wall of a mouse heart was recorded in vivo. To our knowledge, this is the first x-ray diffraction study on a heart in a living body. After the R wave in electrocardiograms, the ratio of the intensities of the equatorial (1,0) and (1,1) reflections decreased for approximately 50 ms from a diastolic value of 2.1 to a minimum of 0.8, and then recovered. The spacing of the (1,0) lattice planes increased for approximately 90 ms from a diastolic value of 37.2 nm to a maximum of 39.1 nm, and then returned to the diastolic level, corresponding to approximately 10% stretch of sarcomere. Stimulation of beta-adrenergic receptor by dobutamine (20 microg/kg/min) accelerated both the decrease in the intensity ratio, which reached a smaller systolic value, and the increase in the lattice spacing. However, the intensity ratio and spacing at the end-diastole were unchanged. The recovery of the lattice spacing during relaxation was also accelerated. The mass transfer to the thin filaments at systole in a beta-stimulated heart was close to the peak value in twitch of frog skeletal muscle at 4 degrees C, showing that the majority of cross-bridges have been recruited with few in reserve.
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- 2006
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39. Xenogenic smooth muscle cell immunization reduces neointimal formation in balloon-injured rabbit carotid arteries
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Tomomi Ueyama, Nobutaka Inoue, Mitsuhiro Yokoyama, Tomofumi Takaya, Seinosuke Kawashima, Ken-ichi Hirata, Tatsuro Ishida, Masakazu Shinohara, Ryuji Toh, and Tomoya Yamashita
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Neointima ,medicine.medical_specialty ,Intimal hyperplasia ,Vascular smooth muscle ,Cell Survival ,Physiology ,medicine.medical_treatment ,Transplantation, Heterologous ,Immunoglobulins ,Apoptosis ,Cell Count ,Biology ,Fibroblast growth factor ,Muscle, Smooth, Vascular ,Receptor, Angiotensin, Type 1 ,Catheterization ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Carotid Stenosis ,Cell Proliferation ,Lagomorpha ,Growth factor ,Anatomy ,musculoskeletal system ,medicine.disease ,biology.organism_classification ,Rats ,medicine.anatomical_structure ,Endocrinology ,Models, Animal ,Hepatocytes ,cardiovascular system ,biology.protein ,Immunization ,Rabbits ,Carotid Artery Injuries ,Tunica Intima ,Cardiology and Cardiovascular Medicine ,tissues ,Platelet-derived growth factor receptor ,Blood vessel - Abstract
Objective: Intimal hyperplasia plays an important role in a variety of types of vascular remodeling, particularly luminal narrowing after vascular injury. The vascular smooth muscle cells (VSMCs) in the neointimal area are a synthetic phenotype and have different epitopes from VSMCs in the normal media. The synthetic VSMCs in the neointima contain various possible antigens that can be targeted by the immune system. In this study, we tried to develop a new immunotherapy, which targets the synthetic VSMCs, for prevention of neointimal formation after angioplasty. Method and results: Rabbits were repeatedly immunized with fixed xenogenic rat cultured VSMCs suspended in adjuvant as immunogens or injected with adjuvant and phosphate-buffered saline (PBS) or rat hepatocytes as controls every 2 weeks for 3 times. One week after the last immunization/injection, balloon injury of the left common carotid artery was performed. Four weeks after the injury, rabbits were euthanized and the neointimal lesion formation was assessed. The mean neointimal area of the PBS-injected, non-immunized group and the rat hepatocyte-immunized, control group was not statistically different (0.339 ± 0.036 and 0.350 ± 0.041 mm2, P = NS). However, immunization with rat VSMCs significantly reduced the intimal lesion area (0.219 ± 0.0286 mm2; P
- Published
- 2005
40. HMG-CoA Reductase Inhibitor Has Protective Effects Against Stroke Events in Stroke-Prone Spontaneously Hypertensive Rats
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Yoichi Miwa, Nobutaka Inoue, Tomoya Yamashita, Masanori Ozaki, Tetsuaki Hirase, Ken-ichi Hirata, Seinosuke Kawashima, Masayuki Namiki, and Mitsuhiro Yokoyama
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Male ,medicine.medical_specialty ,Statin ,Nitric Oxide Synthase Type III ,Pyridines ,medicine.drug_class ,Ischemia ,Infarction ,Blood Pressure ,Rats, Inbred WKY ,Superoxides ,Rats, Inbred SHR ,medicine.artery ,Internal medicine ,medicine ,Animals ,cardiovascular diseases ,Stroke ,Inflammation ,Advanced and Specialized Nursing ,biology ,business.industry ,Brain ,Cerivastatin ,medicine.disease ,Lipids ,Survival Analysis ,Hydroxymethylglutaryl-CoA reductase ,Rats ,Kinetics ,Endocrinology ,Hypertension ,Middle cerebral artery ,HMG-CoA reductase ,biology.protein ,Cardiology ,Blood Vessels ,Neurology (clinical) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Nitric Oxide Synthase ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Background and Purpose— Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur. Methods— We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed. Results— At 14 weeks of age, the incidence (13±3% versus 37±8%; P P P Conclusions— Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.
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- 2003
41. Overexpression of Endothelial Nitric Oxide Synthase in Endothelial Cells Is Protective against Ischemia-Reperfusion Injury in Mouse Skeletal Muscle
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Nobutaka Inoue, Seinosuke Kawashima, Masanori Ozaki, Tetsuaki Hirase, Mitsuhiro Yokoyama, Masayuki Namiki, Tomoya Yamashita, and Ken-ichi Hirata
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Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Nitric Oxide Synthase Type II ,Mice, Transgenic ,Vascular permeability ,Pathology and Forensic Medicine ,Capillary Permeability ,Mice ,Cell Movement ,Ischemia ,Superoxides ,Enos ,Internal medicine ,Leukocytes ,medicine ,Animals ,Muscle, Skeletal ,biology ,Skeletal muscle ,Anatomy ,biology.organism_classification ,medicine.disease ,Leukocyte extravasation ,Nitric oxide synthase ,Endothelial stem cell ,Endocrinology ,medicine.anatomical_structure ,Reperfusion Injury ,biology.protein ,Calcium ,Endothelium, Vascular ,Nitric Oxide Synthase ,Cell Adhesion Molecules ,Reperfusion injury ,Regular Articles - Abstract
Microvascular injury has been proposed to be a main cause of ischemia-reperfusion (I/R) injury. The roles of endothelial nitric oxide synthase (eNOS)-derived NO, a key regulator of vascular function, in I/R injury are incompletely understood. We used transgenic mice overexpressing eNOS in endothelial cells (eNOS-Tg) and their littermates wild-type mice (WT) to investigate the roles of eNOS in I/R injury in skeletal muscle. Superoxide levels in the affected muscles were reduced by approximately 50% in eNOS-Tg compared with WT during reperfusion. In WT, the disassembly of endothelial junctional proteins seen in the early period of reperfusion was recovered in the later phase. These findings were correlated with the increased vascular permeability in vivo. In contrast, eNOS-Tg maintained the endothelial junction assembly as well as vascular permeability during reperfusion. Leukocyte extravasation into tissue and up-regulated expression of adhesion molecules in the reperfused vessels were significantly inhibited in eNOS-Tg. Tissue viability of the affected muscle was decreased in WT time-dependently after reperfusion, whereas eNOS-Tg showed no significant reduction. NOS inhibition completely reversed these protective effects of eNOS overexpression in I/R injury. Thus, eNOS overexpression appears to prevent the I/R injury in skeletal muscle by maintaining vascular integrity.
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- 2002
42. Overexpression of Endothelial Nitric Oxide Synthase Attenuates Cardiac Hypertrophy Induced by Chronic Isoproterenol Infusion
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Nobutaka Inoue, Ken-ichi Hirata, Tomoya Yamashita, Yoshitaka Ohashi, Masanori Ozaki, Seinosuke Kawashima, Mitsuhiro Yokoyama, and Tetsuaki Hirase
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medicine.medical_specialty ,Cardiomegaly ,Mice, Transgenic ,Stimulation ,Nitric oxide ,Muscle hypertrophy ,Mice ,chemistry.chemical_compound ,Atrial natriuretic peptide ,Enos ,Internal medicine ,Isoprenaline ,medicine ,Animals ,Muscle Cells ,biology ,business.industry ,Isoproterenol ,General Medicine ,Adrenergic beta-Agonists ,Hydralazine ,biology.organism_classification ,Nitric oxide synthase ,Endocrinology ,chemistry ,biology.protein ,Nitric Oxide Synthase ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Endogenous nitric oxide (NO) inhibits the contractile response to β-adrenergic stimulation, but its effect on cardiac hypertrophy mediated by β-adrenoceptors remains unclear. The present study was designed to determine whether overproduction of endothelial NO synthase (eNOS) could inhibit cardiac hypertrophy induced by chronic isoproterenol (ISO) infusion (30 mg/kg per day) using eNOS overexpressing (eNOS-Tg) mice and wild-type (WT) mice. In a separate group, WT mice were treated with ISO and hydralazine to decrease blood pressure to the same levels in eNOS-Tg mice. The eNOS expression, NOS activity, and cGMP levels in the heart were remarkably higher in eNOS-Tg mice than in WT mice. ISO increased both heart weight and the heart/body weight ratio, which were significantly attenuated in eNOS-Tg mice compared with WT or hydralazine-treated WT mice. Histological examination revealed that the extent of fibrosis was not significantly different among the 3 groups, and that the increase in myocyte size was more than 10% lower in eNOS-Tg than in the other groups. In addition, up-regulated expression of atrial natriuretic peptide mRNA associated with cardiac hypertrophy was significantly inhibited in eNOS-Tg mice during ISO infusion. These results indicate that endogenous NO might act as a negative modulator for the hypertrophic response to β-adrenergic stimulation. (Circ J 2002; 66: 851 - 856)
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- 2002
43. Regression of atherosclerosis with anti-CD3 antibody via augmenting a regulatory T-cell response in mice
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Kazuyuki Kasahara, Keiko Yodoi, Naoto Sasaki, Yoshihiro Sasaki, Ken-ichi Hirata, Masafumi Takeda, Kenji Nakajima, Tomoya Yamashita, and Tomoyuki Kita
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Male ,medicine.medical_specialty ,CD3 Complex ,Physiology ,Regulatory T cell ,Inflammation ,Antibodies, Monoclonal, Humanized ,T-Lymphocytes, Regulatory ,Immunoglobulin G ,Immune system ,Physiology (medical) ,Internal medicine ,Medicine ,Macrophage ,Animals ,Mice, Knockout ,biology ,business.industry ,Antibodies, Monoclonal ,T lymphocyte ,Atherosclerosis ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Treatment Outcome ,Immunology ,biology.protein ,Animal studies ,Antibody ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Although recent animal studies have investigated the cellular and molecular mechanisms underlying the process of atherosclerosis regression, it remains unknown whether adaptive immune responses including T cells are involved in this process. We investigated the role of T cells in atherosclerosis regression. Methods and results LDL receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to form atherosclerotic lesions and were then changed to a standard diet, and atherosclerosis was assessed 4 weeks later. Just before changing the diet, the mice received an iv injection of anti-CD3 antibody (CD3-Ab) or control immunoglobulin G for 5 consecutive days. CD3-Ab treatment regressed atherosclerosis and decreased the accumulation of macrophages and CD4+ T cells in the plaques. CD3-Ab treatment also dramatically reduced CD4+ T cells and increased the proportion of regulatory T cells (Tregs). Depletion of Tregs by anti-CD25 antibody injection abolished the regression of atherosclerosis seen in CD3-Ab-treated mice, indicating the essential role for Tregs in this process. Conclusion CD3-Ab treatment induced rapid regression of established atherosclerosis via reducing CD4+ T cells and increasing the proportion of Tregs. These findings suggest that therapeutic intervention for T-cell-mediated immune responses may represent a novel strategy to induce atherosclerosis regression in combination with lipid-lowering therapy.
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- 2014
44. Mechanisms of Reduced Nitric Oxide/cGMP–Mediated Vasorelaxation in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase
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Yoshitaka Ohashi, Masanori Ozaki, Mitsuhiro Yokoyama, Tomoya Yamashita, Yoshiyuki Rikitake, Nobutaka Inoue, Hozuka Akita, Ken-ichi Hirata, and Seinosuke Kawashima
- Subjects
medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Endothelium ,Nitric Oxide Synthase Type II ,Mice, Transgenic ,Vasodilation ,Dinoprost ,Nitric Oxide ,Potassium Chloride ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Superoxides ,Enos ,Internal medicine ,Cyclic GMP-Dependent Protein Kinases ,Internal Medicine ,medicine ,Animals ,Cyclic GMP ,biology ,Gene Transfer Techniques ,biology.organism_classification ,Nitric oxide synthase ,NG-Nitroarginine Methyl Ester ,Endocrinology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Guanylate Cyclase ,cardiovascular system ,biology.protein ,Sodium nitroprusside ,Nitric Oxide Synthase ,Protein Kinases ,medicine.drug ,Blood vessel - Abstract
Abstract —NO, constitutively produced by endothelial NO synthase (eNOS), plays a key regulatory role in vascular wall homeostasis. We generated transgenic (Tg) mice overexpressing eNOS in the endothelium and reported the presence of reduced NO-elicited relaxation. The purpose of this study was to clarify mechanisms of the reduced response to NO-mediated vasodilators in eNOS-Tg mice. Thoracic aortas of Tg and control mice were surgically isolated for vasomotor studies. Relaxations to acetylcholine and sodium nitroprusside were significantly reduced in Tg vessels compared with control vessels. Relaxations to atrial natriuretic peptide and 8-bromo-cGMP were also significantly reduced in Tg vessels. Reduced relaxations to these agents were restored by chronic N G -nitro- l -arginine methyl ester treatment. Basal cGMP levels of aortas were higher in Tg mice than in control mice, whereas soluble guanylate cyclase (sGC) activity in Tg vessels was ≈50% of the activity in control vessels. Moreover, cGMP-dependent protein kinase (PKG) protein levels and PKG enzyme activity were decreased in Tg vessels. These observations indicate that chronic overexpression of eNOS in the endothelium resulted in resistance to the NO/cGMP-mediated vasodilators and that at least 2 distinct mechanisms might be involved: one is reduced sGC activity, and the other is a decrease in PKG protein levels. We reported for the first time that increased NO release from the endothelium reduces sGC and PKG activity in mice. These data may provide a new insight into the mechanisms of nitrate tolerance and cross tolerance to nitrovasodilators.
- Published
- 2000
45. Resistance to Endotoxin Shock in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase
- Author
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Ken-ichi Hirata, Mitsuhiro Yokoyama, Tatsuro Ishida, Seinosuke Kawashima, Masaori Ozaki, Tomomi Ueyama, Yoshitaka Ohashi, Nobutaka Inoue, Tomoya Yamashita, and Hozuka Akita
- Subjects
Lipopolysaccharides ,Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Lipopolysaccharide ,Multiple Organ Failure ,Transgene ,Nitric Oxide Synthase Type II ,Blood Pressure ,Mice, Transgenic ,Nitric oxide ,Mice ,chemistry.chemical_compound ,Enos ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Edema ,Cyclic GMP ,Lung ,Aorta ,Nitrites ,Peroxidase ,Nitrates ,biology ,business.industry ,Septic shock ,Cell adhesion molecule ,Organ Size ,medicine.disease ,biology.organism_classification ,Shock, Septic ,Immunity, Innate ,Mice, Inbred C57BL ,Vasodilation ,Nitric oxide synthase ,Endocrinology ,chemistry ,Shock (circulatory) ,Immunology ,biology.protein ,Female ,Hypotension ,Nitric Oxide Synthase ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Granulocytes - Abstract
Background —Nitric oxide (NO) plays a central role in the pathogenesis of septic shock. However, the role of the NO produced by endothelial NO synthase (eNOS) in septic shock is still unclear. We examined the effect of chronic eNOS overexpression and the role of eNOS-derived NO in lipopolysaccharide (LPS)-induced septic shock using eNOS transgenic (Tg) mice. Methods and Results —LPS was intraperitoneally injected into Tg and control mice. No differences existed in the peak plasma nitrate and nitrate levels induced by LPS between the 2 genotypes. In LPS-treated control mice, blood pressure progressively declined and reached 60% of basal levels (from 97±3 to 59±3 mm Hg) 24 hours after LPS injection. In contrast, the blood pressure of LPS-treated Tg mice fell only 15% from basal levels (from 84±4 to 71±4 mm Hg) after the first 6 hours and, thereafter, it remained at this level. LPS-induced increases in the expression of the mRNA of both vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 in the lungs were significantly lower in Tg mice than in control mice. LPS-induced pulmonary leukocyte infiltration and increases in lung water content were also significantly attenuated in Tg mice. Histological examination revealed that lung injury after LPS injection was milder in Tg mice. Furthermore, Tg mice exhibited enhanced survival from LPS-induced septic shock compared with control mice. Conclusions —Chronic eNOS overexpression in the endothelium of mice resulted in resistance to LPS-induced hypotension, lung injury, and death. These effects are associated with the reduced vascular reactivity to NO and the reduced anti-inflammatory effects of NO.
- Published
- 2000
46. Monocyte-to-HDL-cholesterol ratio and left atrial remodelling in atrial fibrillation: author's reply
- Author
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Naoto Sasaki, Atsushi Suzuki, Koji Fukuzawa, Tomoya Yamashita, and Ken-ichi Hirata
- Subjects
medicine.medical_specialty ,CD14 ,Inflammation ,030204 cardiovascular system & hematology ,CD16 ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Medicine ,business.industry ,Cholesterol ,Monocyte ,Atrial fibrillation ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,chemistry ,030220 oncology & carcinogenesis ,Cardiology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Oxidative stress - Abstract
We thank Dr Canpolat1 for his interest in our recent study.2 Many studies have established a strong association between inflammation, oxidative stress, and atrial fibrillation (AF); the pathogenesis and progression of AF seem to be simultaneously influenced by multiple factors.3–5 Canpolat et al. showed in their study that among commonly measured clinical factors, the ‘monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR)’—a combined inflammatory and oxidative stress marker—was independently associated with AF recurrence after cryo-energy ablation and correlated with the left atrial (LA) diameter.6 In our study, we investigated the role of intermediate CD14++CD16+ monocytes in the pathogenesis of AF and showed that a monocyte subgroup, intermediate CD14++CD16+ monocytes, …
- Published
- 2016
47. Circulating intermediate CD14++CD16+monocytes are increased in patients with atrial fibrillation and reflect the functional remodelling of the left atrium
- Author
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Ken-ichi Hirata, Naoto Sasaki, Tomoyuki Nakanishi, Takuo Emoto, Soichiro Yamashita, Ryudo Fujiwara, Koji Fukuzawa, Tomoya Yamashita, Atsushi Suzuki, Akinori Matsumoto, Akihiro Yoshida, Asumi Takei, Hiroki Konishi, and Hirotoshi Ichibori
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,CD14 ,medicine.medical_treatment ,Lipopolysaccharide Receptors ,Catheter ablation ,030204 cardiovascular system & hematology ,CD16 ,GPI-Linked Proteins ,Monocytes ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Predictive Value of Tests ,Physiology (medical) ,Internal medicine ,Atrial Fibrillation ,Natriuretic Peptide, Brain ,Odds Ratio ,medicine ,Humans ,Aged ,Chi-Square Distribution ,Collagen disease ,business.industry ,Monocyte ,Receptors, IgG ,Atrial fibrillation ,Atrial Remodeling ,Middle Aged ,medicine.disease ,Brain natriuretic peptide ,Up-Regulation ,Logistic Models ,030104 developmental biology ,medicine.anatomical_structure ,Case-Control Studies ,Multivariate Analysis ,Cardiology ,Atrial Function, Left ,Female ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
Aims A recent large clinical study demonstrated the association between intermediate CD14++CD16+monocytes and cardiovascular events. However, whether that monocyte subset contributes to the pathogenesis of atrial fibrillation (AF) has not been clarified. We compared the circulating monocyte subsets in AF patients and healthy people, and investigated the possible role of intermediate CD14++CD16+monocytes in the pathophysiology of AF. Methods and results This case–control study included 44 consecutive AF patients without systemic diseases referred for catheter ablation at our hospital, and 40 healthy controls. Patients with systemic diseases, including structural heart disease, hepatic or renal dysfunction, collagen disease, malignancy, and inflammation were excluded. Monocyte subset analyses were performed (three distinct human monocyte subsets: classical CD14++CD16−, intermediate CD14++CD16+, and non-classical CD14+CD16++monocytes). We compared the monocyte subsets and evaluated the correlation with other clinical findings. A total of 60 participants (30 AF patients and 30 controls as an age-matched group) were included after excluding 14 AF patients due to inflammation. Atrial fibrillation patients had a higher proportion of circulating intermediate CD14++CD16+monocytes than the controls (17.0 ± 9.6 vs. 7.5 ± 4.1%, P < 0.001). A multivariable logistic regression analysis demonstrated that only the proportion of intermediate CD14++CD16+monocytes (odds ratio: 1.316; 95% confidence interval: 1.095–1.582, P = 0.003) was independently associated with the presence of AF. Intermediate CD14++CD16+monocytes were negatively correlated with the left atrial appendage flow during sinus rhythm ( r = −0.679, P = 0.003) and positively with the brain natriuretic peptide ( r = 0.439, P = 0.015). Conclusion Intermediate CD14++CD16+monocytes might be closely related to the pathogenesis of AF and reflect functional remodelling of the left atrium.
- Published
- 2016
48. Regulatory T cells in atherogenesis
- Author
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Tomoya Yamashita, Naoto Sasaki, Ken-ichi Hirata, and Masafumi Takeda
- Subjects
business.industry ,Effector ,Biochemistry (medical) ,chemical and pharmacologic phenomena ,Inflammation ,Endogeny ,Immune modulation ,Acquired immune system ,Atherosclerosis ,T-Lymphocytes, Regulatory ,Therapeutic approach ,Immune system ,Immunology ,Internal Medicine ,medicine ,Immune Tolerance ,Animals ,Humans ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Immunologic Tolerance - Abstract
Atherosclerosis is believed to be an inflammatory condition of the arterial wall. It has become apparent that various types of cells of innate and adaptive immunity participate in atherogenesis. T cells are of particular interest because they mediate pathogenic immune responses involved in the acceleration of atherosclerosis. Recent studies from several independent groups indicated that subsets of regulatory T cells (Tregs) actively mediate immunologic tolerance and inhibit atherosclerosis development or progression through the down-regulation of effector T-cell responses. It is likely that there is an imbalance between pathogenic effector T cells and Tregs under atherosclerotic conditions. Recent evidence suggests that in addition to the thymus, gut-associated lymphoid tissues are the main sites for the generation of several subsets of peripherally inducible Tregs. This indicates that intervention in the gut environment to promote an endogenous regulatory immune response may serve as a possible therapeutic approach to suppress atherosclerotic diseases. In this review, we discuss not only the possible role of Tregs in the prevention of atherosclerosis, but also promising strategies to prevent or cure atherosclerotic diseases by promoting an endogenous regulatory immune response, particularly by oral immune modulation.
- Published
- 2012
49. Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions
- Author
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Naoto Sasaki, Masafumi Takeda, Tomoya Yamashita, Ken-ichi Hirata, Masakazu Shinohara, Tomoyuki Kita, Kenji Nakajima, and Tatsuro Ishida
- Subjects
medicine.medical_specialty ,Calcitriol ,Anti-Inflammatory Agents ,Aortic Diseases ,Administration, Oral ,T-Lymphocytes, Regulatory ,chemistry.chemical_compound ,Mice ,Immune system ,Apolipoproteins E ,Internal medicine ,Intestine, Small ,medicine ,Immune Tolerance ,Animals ,IL-2 receptor ,RNA, Messenger ,Cells, Cultured ,Mice, Knockout ,business.industry ,Interleukin-2 Receptor alpha Subunit ,FOXP3 ,Forkhead Transcription Factors ,Dendritic cell ,Dendritic Cells ,Atherosclerosis ,Interleukin-12 ,CD11c Antigen ,Interleukin-10 ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,Gene Expression Regulation ,Interleukin 12 ,B7-1 Antigen ,Female ,B7-2 Antigen ,Lymph Nodes ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,Cholecalciferol ,business ,CD80 ,Spleen ,medicine.drug - Abstract
Objective— To determine whether the administration of an active form of vitamin D 3 (calcitriol) could prevent atherosclerosis through anti-inflammatory actions. Methods and Results— Recent clinical studies have shown that lack of vitamin D 3 is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4 + T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3 + regulatory T cells and a decrease in CD80 + CD86 + dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol–treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c + DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell–dependent manner but also partly because of a decrease in DC maturation. Conclusion— Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis.
- Published
- 2010
50. The effect of the long term aspirin administration on the progress of atherosclerosis in apoE-/- LDLR-/- double knockout mouse
- Author
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Kumi Sakamoto, Tomoya Yamashita, F. Kitagawa, Junichiro Yamamoto, Y. Yamamoto, and John C. Giddings
- Subjects
Apolipoprotein E ,Male ,medicine.medical_specialty ,Time Factors ,Endothelium ,Nitric Oxide Synthase Type III ,Prostaglandin ,Nitric Oxide ,chemistry.chemical_compound ,Mice ,Apolipoproteins E ,Bleeding time ,Internal medicine ,medicine ,Animals ,Antipyretic ,Endothelial dysfunction ,Aorta ,Mice, Knockout ,Aspirin ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Homozygote ,Endothelial Cells ,Hematology ,Arteriosclerosis ,medicine.disease ,Atherosclerosis ,Immunohistochemistry ,Acetylcholine ,Surgery ,Endocrinology ,medicine.anatomical_structure ,Diet, Atherogenic ,Endothelium, Vascular ,medicine.drug - Abstract
We have investigated the effects of differential aspirin doses on atherogenesis. Aspirin was given to homozygous, apoE -/- and LDLR -/- double deficient mice for 12 weeks. The development of arteriosclerosis was determined morphologically by image analysis and endothelial cell function was assessed by measurement of peripheral nitric oxide (NO). Methods ApoE -/- LDLR -/- double knockout mice were bred and maintained with a high fat diet containing aspirin (4 and 40 mg/kg B.W. /day) for twelve weeks. The development of arteriosclerosis was monitored by estimating the total area of atherosclerotic lesions in the entire aorta. Acetylcholine-induced NO release was measured in vivo using electrochemical sensors. The expression of eNOS on the endothelial surface was determined by immuno-staining. Plasma prostaglandin F1α (PGF 1α ), serum thromboxian B 2 (TXB 2 ) and total cholesterol were measured using enzymatic assay. Bleeding time was measured by tail cut method. Results Arteriosclerosis in the 4 mg/kg/day aspirin group was decreased significantly compared with the placebo group, but not in the 40 mg/kg/day aspirin group. Acetylcholine-induced NO release was significantly depressed in the 40 mg/kg/day aspirin group. Immunochemical analysis with anti-eNOS antibody supported these findings. In the 4 mg/kg/day aspirin group, the severe suppression of PGI 2 production was not confirmed in spite of decreasing TXB 2 production, but not in the 40 mg/kg/day aspirin group. Conclusion Our results suggest that endothelial dysfunction with low dose aspirin improved, reduced progression of atherosclerosis in apoE -/- and LDLR -/- double deficient mice and provides a pathophysiological basis for the beneficial effects of aspirin in atherosclerosis, and low doses appeared to be more efficient than high doses.
- Published
- 2009
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