39 results on '"SHIGANG QIAO"'
Search Results
2. Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy
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Wei Li, Xinqi Lou, Yingjie Zha, Yinyin Qin, Jun Zha, Lei Hong, Zhanli Xie, Shudi Yang, Chen Wang, Jianzhong An, Zhenhao Zhang, and Shigang Qiao
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diabetic cardiomyopathy ,liver fibrosis ,retinal regeneration ,rat ,rabbit ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Myocardial fibrosis is the characteristic pathology of diabetes-induced cardiomyopathy. Therefore, an in-depth study of cardiac heterogeneity and cell-to-cell interactions can help elucidate the pathogenesis of diabetic myocardial fibrosis and identify treatment targets for the treatment of this disease. In this study, we investigated intercellular communication drivers of myocardial fibrosis in mouse heart with high-fat-diet/streptozotocin-induced diabetes at single-cell resolution. Intercellular and protein–protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells revealed critical changes in ligand–receptor interactions such as Pdgf(s)–Pdgfra and Efemp1–Egfr, which promote the development of a profibrotic microenvironment during the progression of and confirmed that the specific inhibition of the Pdgfra axis could significantly improve diabetic myocardial fibrosis. We also identified phenotypically distinct Hrchi and Postnhi fibroblast subpopulations associated with pathological extracellular matrix remodeling, of which the Hrchi fibroblasts were found to be the most profibrogenic under diabetic conditions. Finally, we validated the role of the Itgb1 hub gene-mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the results through AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers involved in pathological extracellular matrix remodeling during diabetic myocardial fibrosis.
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- 2023
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3. Omicron adopts a different strategy from Delta and other variants to adapt to host
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Xiaohong Du, Haijun Tang, Long Gao, Zhao Wu, Fang Meng, Ruhong Yan, Shigang Qiao, Jianzhong An, Chen Wang, and F. Xiao-Feng Qin
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Medicine ,Biology (General) ,QH301-705.5 - Published
- 2022
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4. Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling
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Yanan Liu, Shelley L. Baumgardt, Juan Fang, Yang Shi, Shigang Qiao, Zeljko J. Bosnjak, Jeannette Vásquez-Vivar, Zhengyuan Xia, David C. Warltier, Judy R. Kersten, and Zhi-Dong Ge
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Medicine ,Science - Abstract
Abstract GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction.
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- 2017
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5. N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.
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Tingting Wang, Shigang Qiao, Shaoqing Lei, Yanan Liu, Kwok F J Ng, Aimin Xu, Karen S L Lam, Michael G Irwin, and Zhengyuan Xia
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Medicine ,Science - Abstract
Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes.Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P
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- 2011
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6. Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats
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Chen Wang, Huan-Qiu Li, Guizhen Ao, Shigang Qiao, Wen-Jie Zhao, Hui-Ling Zhang, and Jianzhong An
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Male ,Programmed cell death ,Cardiotonic Agents ,Indoles ,Cathepsin L ,Necroptosis ,Primary Cell Culture ,Myocardial Infarction ,Ischemia ,Myocardial Reperfusion Injury ,Protein Serine-Threonine Kinases ,Pharmacology ,Cathepsin B ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Lactate dehydrogenase ,Autophagy ,medicine ,Animals ,Myocytes, Cardiac ,Cardioprotection ,Cell Death ,Kinase ,Chemistry ,Hemodynamics ,Imidazoles ,General Medicine ,medicine.disease ,Molecular Docking Simulation ,Animals, Newborn ,Structural Homology, Protein ,Receptor-Interacting Protein Serine-Threonine Kinases ,Beclin-1 ,Microtubule-Associated Proteins ,Reperfusion injury - Abstract
Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.
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- 2021
7. Characterization of SARS-CoV-2 Variants N501Y.V1 and N501Y.V2 Spike on Viral Infectivity
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Haijun Tang, Long Gao, Zhao Wu, Fang Meng, Xin Zhao, Yun Shao, Xiaohua Shi, Shigang Qiao, Jianzhong An, Xiaohong Du, and F. Xiao-Feng Qin
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Microbiology (medical) ,viruses ,medicine.medical_treatment ,Immunology ,Endocytosis ,medicine.disease_cause ,Microbiology ,thermal stability ,Virus ,Cellular and Infection Microbiology ,medicine ,Pathogen ,Original Research ,Infectivity ,Mutation ,Protease ,biology ,SARS-CoV-2 ,infectivity ,Wild type ,biology.organism_classification ,Virology ,QR1-502 ,Infectious Diseases ,Vesicular stomatitis virus ,N501Y.V2 ,N501Y.V1 - Abstract
SARS-coronavirus 2 (SARS-CoV-2), pathogen of coronavirus disease 2019 (COVID-19), is constantly evolving to adapt to the host and evade antiviral immunity. The newly emerging variants N501Y.V1 (B.1.1.7) and N501Y.V2 (B.1.351), first reported in the United Kingdom and South Africa respectively, raised concerns due to the unusually rapid global spread. The mutations in spike (S) protein may contribute to the rapid spread of these variants. Here, with a vesicular stomatitis virus (VSV)-based pseudotype system, we demonstrated that the pseudovirus bearing N501Y.V2 S protein has higher infection efficiency than pseudovirus with wildtype (WT) and D614G S protein. Moreover, pseudovirus with N501Y.V1 or N501Y.V2 S protein has better thermal stability than WT and D614G, suggesting these mutations of variants may increase the stability of SARS-CoV-2 S protein and virion. However, the pseudovirus bearing N501Y.V1 or N501Y.V2 S protein has similar sensitivity to inhibitors of protease and endocytosis with WT and D614G. These findings could be of value in preventing the spread of virus and developing drugs for emerging SARS-CoV-2 variants.
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- 2021
8. Astrocyte-Derived TNF-α Activated Platelets Promote Cerebral Ischemia/Reperfusion Injury by Regulating RIP1/RIP3/AKT Signaling Pathway
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Jianzhong An, Wei Li, Shigang Qiao, Jiaqi Xu, Jun Zha, Chen Wang, Zhanli Xie, and Dengping Liu
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medicine.anatomical_structure ,Akt/PKB signaling pathway ,Chemistry ,medicine ,Ischemia ,Platelet activation ,Pharmacology ,medicine.disease ,Reperfusion injury ,Astrocyte - Abstract
Ischemic stroke is a type of clinical syndrome caused by disruption of blood flow into the cerebral tissues, and is associated with high disability and mortality rates. Studies have established a pathological role of platelets in cerebral ischemia/reperfusion (I/R) injury, although the underlying mechanisms remain largely unclear. In the present study, we induced I/R in a mouse model via middle cerebral artery occlusion and reperfusion (MCAO/R), and analyzed the transcriptomic profiles of the ipsilateral and contralateral cortices by RNA-seq. We found that cerebral I/R injury induced platelet invasion and accumulation in the cerebral cortex by stimulating TNF-α secretion from the activated astrocytes in the ischemic region. TNF-α enhanced platelet reactivity through the RIP1/RIP3/AKT pathway. Furthermore, inoculation of TNF-α-stimulated platelets aggravated I/R injury in mice, whereas administration of anti-TNF-α antibodies at the onset of reperfusion alleviated ischemic damage. RNA-seq further showed that AP-1 transcriptionally activated TNF-α in the I/R-injured cortex by directly binding to the promoter region. These findings provide novel insights into the pathological role of platelets induced by reactive astrocyte-derived TNF-α in cerebral I/R injury.
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- 2021
9. EIT-derived PEEP Vs other PEEP titration strategies for patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis
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Yanjun Deng, Shigang Qiao, Hua Li, Mengnan Yu, Chen Wang, Lingyan Jiang, and Jun Zha
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business.industry ,Meta-analysis ,Anesthesia ,Medicine ,Acute respiratory distress ,business - Published
- 2021
10. Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells
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Jianzhong An, Lei Hong, Chen Wang, Shigang Qiao, and Yingjie Zha
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QH301-705.5 ,Pharmacology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,Palmitic acid ,chemistry.chemical_compound ,folic acid ,Lactate dehydrogenase ,medicine ,diabetic cardiomyopathy ,Molecular Biosciences ,Viability assay ,hippo signal pathway ,Biology (General) ,Cell damage ,Molecular Biology ,Original Research ,YAP1 ,Hippo signaling pathway ,pyroptosis ,Pyroptosis ,Streptozotocin ,medicine.disease ,chemistry ,type 2 diabetes ,medicine.drug - Abstract
Diabetic cardiomyopathy (DCM) is the leading cause of death in diabetic patients. Folic acid has a protective effect on diabetes-induced cardiomyocyte damage. The aim of this study was to explore the effects of folic acid on cardiomyocytes cultured under high glucose and fat (HGF) conditions and type 2 diabetes mellitus (T2DM) mice, and elucidate the underlying mechanisms. Bioinformatics analysis was used to identify the potential drugs through the Drug-Gene Interaction database. H9C2 cardiomyocytes were cultured with 30 mM glucose and 500 nM palmitic acid in the presence or absence of folic acid or YAP1 inhibitor (verteporfin) or YAP1 siRNA. The cell viability and lactate dehydrogenase (LDH) release were measured using specific assay kits. Pyroptosis was detected by flow cytometry. The concentrations of IL-1β and IL-18 in the supernatants were measured by ELISA. The NLRP3, ASC and caspase-1 mRNA levels were detected by qRT-PCR and that the proteins expression of NLRP3, ASC, cleaved caspase-1 (p10), caspase-1, YAP1, p-YAP1, LATS1 and P-LATS1 were detected by Western blotting. C57BL/6 mice were fed with high fat diet (HFD) combined with streptozotocin (STZ) intraperitoneally to establish a T2DM model, folic acid or PBS treatment for 8 weeks by oral gavage, blood glucose and body weight were measured every 4 weeks, mouse heart tissue was used to detect pyroptosis and hippo signaling pathway related protein expression. We identified 427 differentially expressed genes in the cardiac tissues of high fat diet + streptozotocin mice, among the 30 most significantly DEGs, folic acid was predicted to be the most likely therapeutic drug. Folic acid alleviated HGF-induced cell damage in vitro and in vivo by decreasing activation of the Hippo pathway, as indicated by lower LDH release and increased cell viability, and decreased expression of NLRP3, ASC, cleaved caspase-1, IL-1β, IL-18, p-YAP and p-LATS. Verteporfin or YAP1 siRNA neutralized the protective effect of folic acid by reversing YAP1-induced pyroptosis. Folic acid reduced NLRP3 inflammasome-mediated pyroptosis by down-regulating the Hippo signaling pathway, thereby effectively reducing T2DM-induced damage in H9C2 cells and animals.
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- 2021
11. Ratio of Optic Nerve Sheath Diameter to Eyeball Transverse Diameter by Ultrasound Can Predict Intracranial Hypertension in Traumatic Brain Injury Patients: A Prospective Study
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Chen Wang, Jie Du, Yanjun Deng, Shigang Qiao, Hua Li, Qingya Xu, and Mengnan Yu
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Receiver operating characteristic ,Traumatic brain injury ,business.industry ,medicine.medical_treatment ,Ultrasound ,Area under the curve ,030208 emergency & critical care medicine ,Critical Care and Intensive Care Medicine ,medicine.disease ,Intensive care unit ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,medicine ,Neurology (clinical) ,Nuclear medicine ,business ,Prospective cohort study ,030217 neurology & neurosurgery ,Craniotomy ,Intracranial pressure - Abstract
Measuring optic nerve sheath diameter (ONSD), an indicator to predict intracranial hypertension, is noninvasive and convenient, but the reliability of ONSD needs to be improved. Instead of using ONSD alone, this study aimed to evaluate the reliability of the ratio of ONSD to eyeball transverse diameter (ONSD/ETD) in predicting intracranial hypertension in traumatic brain injury (TBI) patients. We performed a prospective study on patients admitted to the Surgery Intensive Care Unit. The included 52 adults underwent craniotomy for TBI between March 2017 and September 2018. The ONSD and ETD of each eyeball were measured by ultrasound and computed tomography (CT) scan within 24 h after a fiber optic probe was placed into lateral ventricle. Intracranial pressure (ICP) > 20 mmHg was regarded as intracranial hypertension. The correlations between invasive ICP and ultrasound-ONSD/ETD ratio, ultrasound-ONSD, CT-ONSD/ETD ratio, and CT-ONSD were each analyzed separately. Ultrasound measurement was successfully performed in 94% (n = 49) of cases, and ultrasound and CT measurement were performed in 48% (n = 25) of cases. The correlation efficiencies between ultrasound-ONSD/ETD ratio, ultrasound-ONSD, CT-ONSD/ETD ratio, and ICP were 0.613, 0.498, and 0.688, respectively (P
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- 2019
12. Therapeutic Effects of Ultrasound-Guided Percutaneous Laser Ablation for Primary Thyroid Microcarcinoma
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Zheng Kun, Feng Zhou, Sun Xingwei, Xing Fan, Shigang Qiao, Jun Gu, Qin Wu, and Zepeng Yu
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medicine.medical_specialty ,Laser ablation ,medicine.anatomical_structure ,Text mining ,Percutaneous ,genetic structures ,business.industry ,Thyroid ,Therapeutic effect ,Medicine ,Radiology ,business ,Ultrasound guided - Abstract
Background: Ultrasound-guided percutaneous laser ablation, as a minimally invasive ablation method, has been widely used in the treatment of benign and malignant tumors. The objective of the current study is to determine the efficacy and safety of ultrasound-guided percutaneous laser ablation (PLA) for unifocal papillary thyroid micro carcinomas (PTMC).Methods: A total of 18 patients were included in this study. Patients with a single PTMC were treated via the PLA method, and postoperative complications, tumor size and recurrence rate were followed up and recorded.Results: Data suggested that three patients underwent a secondary ablation, and the remaining 15 patients underwent a single ablation without serious complications. No recurrence or metastasis was found among the follow-up patients, and the tumor sizes decreased significantly from 12 months following PLA treatment.Conclusions: Ultrasound-guided PLA is a new therapeutic means that can be used as an alternative to PTMC treatment.
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- 2021
13. [Corrigendum] Sevoflurane post‑conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phosphorylated NHE1 levels
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Ming Ying, Qin Shao, Haorong Wu, Chen Wang, Hong Xie, Jianfang Cao, Shigang Qiao, Ying Sun, and Jiang Zhu
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medicine.medical_specialty ,biology ,Ischemia ,General Medicine ,medicine.disease ,Sevoflurane ,Nitric oxide ,Nitric oxide synthase ,chemistry.chemical_compound ,Endocrinology ,Biochemistry ,Mitochondrial permeability transition pore ,chemistry ,Apoptosis ,Internal medicine ,Genetics ,medicine ,biology.protein ,NAD+ kinase ,Reperfusion injury ,medicine.drug - Abstract
The protective effects of sevoflurane post-conditioning against myocardial ischemia/reperfusion (I/R) injury (MIRI) have been previously reported. However, the mechanisms responsible for these protective effects remain elusive. In this study, in order to investigate the molecular mechanisms responsible for the protective effects of sevoflurane post-conditioning on isolated rat hearts subjected to MIRI, Sprague-Dawley rat hearts were randomly divided into the following 6 groups: i) the sham-operated control; ii) 2.5% sevoflurane; iii) ischemia/reperfusion (I/R); iv) 2.5% sevoflurane post-conditioning plus I/R; v) 2.5% sevoflurane post-conditioning + NG-nitro-L-arginine methyl ester (L-NAME) plus I/R; and vi) L-NAME plus I/R. The infarct size was measured using 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Additionally, the myocardial nitric oxide (NO), NO synthase (NOS) and nicotinamide adenine dinucleotide (NAD+) levels were determined. Autophagosomes and apoptosomes in the myocardium were detected by transmission electron microscopy. The levels of Bcl-2, cleaved caspase-3, Beclin-1, microtubule-associated protein light chain 3 (LC3)‑I/II, Na+/H+ exchanger 1 (NHE1) and phosphorylated NHE1 protein were measured by western blot analysis. NHE1 mRNA levels were measured by reverse transcription-quantitative polymerase chain reaction. Compared with the I/R group, 15 min of exposure to 2.5% sevoflurane during early reperfusion significantly decreased the myocardial infarct size, the autophagic vacuole numbers, the NHE1 mRNA and protein expression of cleaved caspase-3, Beclin-1 and LC3-I/II. Post-conditioning with 2.5% sevoflurane also increased the NO and NOS levels and Bcl-2 protein expression (p
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- 2021
14. Cholinergic receptors play a role in the cardioprotective effects of anesthetic preconditioning: Roles of nitric oxide and the CaMKKβ/AMPK pathway
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Yang Yang, Jie Wang, Chen Wang, Shigang Qiao, Jianzhong An, Ying Li, and Lei Hong
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Cardioprotection ,Cancer Research ,AMPK ,Articles ,General Medicine ,Pharmacology ,Nicotinic acetylcholine receptor ,chemistry.chemical_compound ,Immunology and Microbiology (miscellaneous) ,chemistry ,Muscarinic acetylcholine receptor ,medicine ,Cholinergic ,Hexamethonium ,Acetylcholine ,medicine.drug ,Acetylcholine receptor - Abstract
Vagus nerve activation may have important therapeutic significance for myocardial ischemia-reperfusion (IR) injury. Nitric oxide (NO) plays a vital role in the cardioprotective effects of anesthetic preconditioning (APC). Moreover, acetylcholine (ACh) prevents cardiomyocyte damage by activating AMP-activated protein kinase (AMPK) and increasing the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase β (CaMKKβ). The aim of the present study was to determine whether APC could protect heart function by antagonizing IR damage via the cholinergic system. It was hypothesized that the NO synthase (NOS)/CaMKKβ/AMPK pathway might be involved in the cardioprotective effects induced by cholinergic receptor activation. Isolated rat hearts were subjected to ischemia for 30 min followed by 120 min of reperfusion. Volatile anesthetic sevoflurane (3.5%) was administered for 15 min before ischemia, then rinsed for 15 min. The muscarinic acetylcholine receptor (mAChR) antagonist atropine (ATR; 100 nM) and the nicotinic acetylcholine receptor (nAChR) antagonist hexamethonium (HEM; 50 µM) were administered 10 min before APC. Both mAChR and nAChR were involved in APC-induced cardioprotection. ATR and HEM treatment both abolished the protective effects of APC on IR damage in isolated hearts, demonstrating the importance of cholinergic receptors in the protection mechanism of APC. The present study thus suggests that APC plays a cardioprotective role, in part, by regulating neurohumoral pathways. In addition, there may be functional coupling between the two cholinergic receptors, and the NOS and CaMKKβ/AMPK pathways may play roles in shared pathways that mediate the cardioprotective effects of APC. These findings may provide insight into potential new mechanisms of APC-induced cardioprotection against IR injury.
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- 2020
15. Cardioprotective effects of triiodothyronine supplementation against ischemia reperfusion injury by preserving calcium cycling proteins in isolated rat hearts
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Zhiping Xu, Lichao Fang, Lijun Liu, Jian Lu, Jianzhong An, Lei Hong, and Shigang Qiao
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0301 basic medicine ,High-energy phosphate ,Cancer Research ,medicine.medical_specialty ,Ischemia ,Pharmacology ,Creatine ,Ryanodine receptor 2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,Internal medicine ,medicine ,Triiodothyronine ,Oncogene ,business.industry ,Cancer ,Articles ,General Medicine ,Cell cycle ,medicine.disease ,Molecular medicine ,Phospholamban ,030104 developmental biology ,Endocrinology ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,cardiovascular system ,Triphosphatase ,business ,Corrigendum ,Reperfusion injury - Abstract
Hypothyroidism is associated with profound left ventricular dysfunction. Triiodothyronine (T(3)) supplementation may improve cardiac function after ischemic reperfusion (I/R) injury. In the present study, the effect of T(3) on major calcium cycling proteins and high-energy phosphate content during I/R was evaluated. Isolated perfused rat hearts were divided into 5 groups: Sham Control (Sham, n=10), Control (n=8), T(3) 10 nM (T(3)−10, n=10), T(3) 25 nM (T(3)−25, n=10) and T(3) 50 nM (T(3)−50, n=10). T(3) was administrated for 60 min before 30 min of ischemia and 120 min of reperfusion. The protein contents of Ca(2+)-release channels (RyR2), Ca(2+)-adenosine triphosphatase (SERCA2a), phospholamban (PLB), sarcolemmal Ca(2+)-adenosine triphosphatase (PMCA) and sodium-calcium exchanger (NCX), as well as the high-energy phosphate content in heart tissues were measured by western blot analysis. The results revealed that T(3) improved the contractile recovery (left ventricular developed pressure; +dP/dt, -dP/dt) after I/R. Western blotting assays demonstrated that I/R depressed the contents of RYR2, SERCA2a and phosphorylated RYR2 and PLB; there were no effects on the contents of PLB, PMCA and NCX. T(3) reversed I/R-induced degradation of RyR2 and SERCA2a, restored the phosphorylation of RyR2 and PLB, and preserved the high-energy phosphate contents of ATP and creatine phosphate. T(3) supplementation protected the heart against I/R injury via the preservation of Ca(2+)-cycling proteins and high-energy phosphate content.
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- 2020
16. Sevoflurane Preconditioning Confers Delayed Cardioprotection by Upregulating AMP-Activated Protein Kinase Levels to Restore Autophagic Flux in Ischemia-Reperfusion Rat Hearts
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Shigang Qiao, Chen Wang, Lei Hong, Jianzhong An, and Ying Sun
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Male ,China ,Cardiotonic Agents ,Myocardial Infarction ,Myocardial Ischemia ,Myocardial Reperfusion Injury ,AMP-Activated Protein Kinases ,030204 cardiovascular system & hematology ,Pharmacology ,Rats, Sprague-Dawley ,Sevoflurane ,03 medical and health sciences ,0302 clinical medicine ,AMP-activated protein kinase ,Autophagy ,medicine ,Animals ,Myocytes, Cardiac ,Phosphorylation ,Ischemic Preconditioning ,Protein kinase A ,Cardioprotection ,biology ,Chemistry ,Myocardium ,Animal Study ,Cytochrome c ,AMPK ,General Medicine ,medicine.disease ,Rats ,Oxidative Stress ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Ischemic Preconditioning, Myocardial ,biology.protein ,Reperfusion injury ,Flux (metabolism) - Abstract
BACKGROUND Volatile anesthetic preconditioning confers delayed cardioprotection against ischemia/reperfusion injury (I/R). AMP-activated protein kinase (AMPK) takes part in autophagy activation. Furthermore, autophagic flux is thought to be impaired after I/R. We hypothesized that delayed cardioprotection can restore autophagic flux by activating AMPK. MATERIAL AND METHODS All male rat hearts underwent 30-min ischemia and 120-min reperfusion with or without sevoflurane exposure. AMPK inhibitor compound C (250 μg/kg, iv) was given at the reperfusion period. Autophagic flux blocker chloroquine (10 mg/kg, ip) was administrated 1 h before the experiment. Myocardial infarction, nicotinamide adenine dinucleotide (NAD⁺) content, and cytochrome c were measured. To evaluate autophagic flux, the markers of microtubule-associated protein 1 light chain 3 (LC3) I and II, P62 and Beclin 1, and lysosome-associated membrane protein-2 (LAMP 2) were analyzed. RESULTS The delayed cardioprotection enhanced post-ischemic AMPK activation, reduced infarction, CK-MB level, NAD⁺ content loss and cytochrome c release, and compound C blocked these effects. Sevoflurane restored impaired autophagic flux through a lower ratio of LC3II/LC3I, downregulation of P62 and Beclin 1, and higher expression in LAMP 2. Consistently, compound C inhibited these changes of autophagy flux. Moreover, chloroquine pretreatment abolished sevoflurane-induced infarct size reduction, CK-MB level, NAD⁺ content loss, and cytochrome c release, with concomitant increase the ratios of LC3II/LC3I and levels of P62 and Beclin 1, but p-AMPK expression was not downregulated by chloroquine. CONCLUSIONS Sevoflurane exerts a delayed cardioprotective effects against myocardial injury in rats by activation of AMPK and restoration of I/R-impaired autophagic flux.
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- 2020
17. NOS cofactor tetrahydrobiopterin contributes to anesthetic preconditioning induced myocardial protection in the isolated ex�vivo rat heart
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Tuanjie Che, Jie Sun, Jianzhong An, Shigang Qiao, Lei Hong, Amadou K.S. Camara, and Chen Wang
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Male ,0301 basic medicine ,Cardiac function curve ,Nitric Oxide Synthase Type III ,GTP cyclohydrolase I ,Ischemia ,Myocardial Reperfusion Injury ,Pharmacology ,Nitric oxide ,Rats, Sprague-Dawley ,Sevoflurane ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genetics ,medicine ,Animals ,HSP90 Heat-Shock Proteins ,Anesthetics ,Cardioprotection ,biology ,Superoxide ,Heart ,General Medicine ,Tetrahydrobiopterin ,medicine.disease ,Biopterin ,Rats ,Nitric oxide synthase ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,medicine.drug - Abstract
Anesthetic preconditioning (APC) may decrease the myocardium injury nearly 50% following ischemia/reperfusion (I/R) by enhancing recovery of cardiac function, reducing myocardial enzyme release and lowering infarct size when utilized as pretreatment or posttreatment agents. I/R increases nitric oxide (NO) production through endothelial NO synthase (NOS3) and heat shock protein 90 (HSP90). The present study aimed to observe the role of BH4 availability and the association of HSP90 with NOS3 in APC‑mediated cardioprotection against I/R injury. Isolated rat hearts were subjected to no‑flow ischemia for 30 min and reperfusion for 120 min. Sevoflurane (3.5%) was administered for 15 min followed by a 15 min washout prior to ischemia. 2,4-Diamino-6-hydroxypyrimidine (DAHP) or sepiapterin (SP) was administered for 40 min until the onset of ischemia. The results revealed that compared with pre‑ischemic basal levels, BH4 levels decreased and BH2 levels increased following I/R. BH4 levels were significantly increased and BH2 levels were significantly decreased in the APC + I/R hearts compared with the I/R group hearts. The BH4:BH2 ratio in the APC‑treated hearts was also increased compared with that in the I/R group hearts. SP increased the recovery of contractile function and the production of NO, and decreased the production of superoxide anion (O2·‑) in I/R heart, but did not elicit these effects in APC‑treated hearts. DAHP treatment inhibited the APC‑mediated recovery of contractile function, increased O2·‑ levels and decreased NO production, but had no effect in I/R hearts. The cardioprotection of APC was demonstrated to be modulated by the BH4 precursor SP, which increased BH4 levels, or DAHP, which inhibited GTP cyclohydrolase I. Both APC and SP treatments increased the combination of HSP90 and NOS3, which improved the NOS3 activity and function. The results suggested that BH4, which servesas a cofactor for NOS, mediated the resistance of APC to I/R injury by promoting the binding of HSP90 and NOS3.
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- 2019
18. The Effect of Mitochondrial Complex I-Linked Respiration by Isoflurane Is Independent of Mitochondrial Nitric Oxide Production
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Chen Wang, Fuqi Xu, Jianzhong An, Shigang Qiao, Yanjun Deng, and Hua Li
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Male ,0301 basic medicine ,Urology ,Myocardial Ischemia ,Mitochondrion ,Nitric Oxide ,Mitochondria, Heart ,Nitric oxide ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Respiration ,Animals ,Medicine ,Cardioprotection ,Original Paper ,Isoflurane ,business.industry ,Myocardium ,Snap ,Rats ,Disease Models, Animal ,Adenosine diphosphate ,030104 developmental biology ,chemistry ,Anesthetics, Inhalation ,Ischemic Preconditioning, Myocardial ,Anesthetic ,Biophysics ,Cardiology and Cardiovascular Medicine ,business ,Oxidation-Reduction ,medicine.drug - Abstract
Background: Anesthetic preconditioning (APC) of the myocardium is mediated in part by reversible alteration of mitochondrial function. Nitric oxide (NO) inhibits mitochondrial respiration and may mediate APC-induced cardioprotection. In this study, the effects of isoflurane on different states of mitochondrial respiration during the oxidation of complex I-linked substrates and the role of NO were investigated. Methods: Mitochondria were isolated from Sprague-Dawley rat hearts. Respiration rates were measured polarographically at 28ºC with a computer-controlled Clark-type O2 electrode in the mitochondria (0.5 mg/mL) with complex I substrates glutamate/malate (5 mM). Isoflurane (0.25 mM) was administered before or after adenosine diphosphate (ADP)-initiated state 3 respiration. The NO synthase (NOS) inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 μM) and the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1 μM) were added before or after the addition of ADP. Results: Isoflurane administered in state 2 increased state 2 respiration and decreased state 3 respiration. This attenuation of state 3 respiration by isoflurane was similar when it was given during state 3. L-NIO did not alter mitochondrial respiration or the effect of isoflurane. SNAP only, added in state 3, decreased state 3 respiration and enhanced the isoflurane-induced attenuation of state 3 respiration. Conclusion: Isoflurane has clearly distinguishable effects on different states of mitochondrial respiration during the oxidation of complex I substrates. The uncoupling effect during state 2 respiration and the attenuation of state 3 respiration may contribute to the mechanism of APC-induced cardioprotection. These effects of isoflurane do not depend on endogenous mitochondrial NO, as the NOS inhibitor L-NIO did not alter the effects of isoflurane on mitochondrial respiration.
- Published
- 2018
19. Effects of isoflurane on complex II‑associated mitochondrial respiration and reactive oxygen species production: Roles of nitric oxide and mitochondrial KATP channels
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Shigang Qiao, Junan Wang, Chen Wang, Tuanjie Che, Hua Li, Jianzhong An, and Jie Sun
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Potassium Channels ,Cell Respiration ,Mitochondrion ,Nitric Oxide ,Biochemistry ,Rhodamine 123 ,Nitric oxide ,Electron Transport ,03 medical and health sciences ,chemistry.chemical_compound ,Oxygen Consumption ,0302 clinical medicine ,Respiration ,Genetics ,medicine ,Animals ,Molecular Biology ,Membrane Potential, Mitochondrial ,chemistry.chemical_classification ,Reactive oxygen species ,Isoflurane ,Electron Transport Complex II ,Hydrogen Peroxide ,Rotenone ,Mitochondria ,Rats ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Biophysics ,Molecular Medicine ,Reactive Oxygen Species ,Respiration rate ,medicine.drug - Abstract
Volatile anesthetics may protect the heart against ischemia‑reperfusion injury via the direct action on mitochondrial complexes and by regulating the production of reactive oxygen species (ROS). Recently, we reported that isoflurane induced the attenuation of mitochondrial respiration caused by complex I substrates. This process was not associated with endogenous production of mitochondrial nitric oxide (NO). In the present study, we investigated the effects of isoflurane on mitochondrial respiration and ROS production using complex II substrates. The detailed mechanism of these effects was explored with regards to NO production and the expression of mitochondrial ATP‑dependent K+ (mKATP) channels. Mitochondria were isolated from the heart of Sprague‑Dawley rats. The respiratory rates of mitochondria (0.5 mg/ml) were measured via polarography at 28˚C with computer‑controlled Clark‑type O2 electrodes. The complex II substrate succinate (5 mM) was used; 0.25 mM of isoflurane was administered prior to ADP‑initiated state 3 respiration. The mitochondrial membrane potential (ΔΨm) was measured under treatment with the substrate succinate, or succinate in the presence of the complex I inhibitor rotenone. The detection was achieved in a cuvette‑based spectrophotometer operating at wavelengths of 503 nm (excitation) 527 nm (emission) in the presence of 50 nM of the fluorescent dye rhodamine 123. The H2O2 release rates in the mitochondria were measured spectrophotometrically with succinate, or succinate and rotenone using the fluorescent dye Amplex red (12.5‑25 µM). The results indicated that isoflurane increased the state 3 and 4 respiration rates caused by succinate, which were higher than those noted in the control group in the presence of succinate alone. The NOS inhibitor L‑NIO or the NO‑sensitive guanylyl cyclase 1H‑[1,2,4]oxadiazolo[4,3‑a]quinoxalin‑1‑one did not inhibit the increase in the respiration rate (state 3) induced by isoflurane. The ROS scavengers SPBN and manganese (III) tetrakis (4‑benzoic acid) porphyrin chloride inhibited the increase in the respiration rate (state 3 and 4) induced by isoflurane. This effect was not noted for the putative KATP channel blockers 5‑hydroxydecanoic acid and glibenclamide. Isoflurane caused a greater decrease in the concentration of H2O2 during ADP‑initiated state 3 respiration, and L‑N5‑(1‑Iminoethyl)‑ornithine did not inhibit this effect. In conclusion, isoflurane was determined to modulate mitochondrial respiration and ROS production caused by the complex II substrate succinate. These effects were independent of endogenous mitochondrial NO generation and mitochondrial KATP channel opening.
- Published
- 2019
20. Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling
- Author
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Michael G. Irwin, Lu Zhou, Yafeng Wang, Zhengyuan Xia, Wating Su, Shigang Qiao, Shaoqing Lei, Zhongyuan Xia, and Bo Zhao
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Aging ,Cardiotonic Agents ,Article Subject ,Caveolin 3 ,030204 cardiovascular system & hematology ,Pharmacology ,medicine.disease_cause ,Biochemistry ,Wortmannin ,Rats, Sprague-Dawley ,Remifentanil ,03 medical and health sciences ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Caveolae ,medicine ,Animals ,Humans ,lcsh:QH573-671 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cardioprotection ,Gene knockdown ,lcsh:Cytology ,Cell Biology ,General Medicine ,Janus Kinase 2 ,Rats ,Analgesics, Opioid ,Oxidative Stress ,030104 developmental biology ,chemistry ,Hyperglycemia ,cardiovascular system ,Proto-Oncogene Proteins c-akt ,Oxidative stress ,Research Article - Abstract
Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2-, and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.
- Published
- 2019
21. Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism
- Author
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An Wang, Lei Hong, Bo Sun, Shigang Qiao, Jianzhong An, Jia Qiu, Hui-Ling Zhang, Chen Wang, and Ying Sun
- Subjects
0301 basic medicine ,Male ,Nitric Oxide Synthase Type III ,Ischemia ,Myocardial Reperfusion Injury ,Nitric Oxide Synthase Type I ,Pharmacology ,Nitric Oxide ,Sevoflurane ,Article ,Nitric oxide ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,medicine ,Autophagy ,Animals ,Pharmacology (medical) ,Cardioprotection ,biology ,Chemistry ,Myocardium ,General Medicine ,medicine.disease ,Nitric oxide synthase ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Reperfusion injury ,Ex vivo ,medicine.drug - Abstract
Volatile anesthetics improve postischemic cardiac function and reduce infarction even when administered for only a brief time at the onset of reperfusion. A recent study showed that sevoflurane postconditioning (SPC) attenuated myocardial reperfusion injury, but the underlying mechanisms remain unclear. In this study, we examined the effects of sevoflurane on nitric oxide (NO) release and autophagic flux during the myocardial ischemia/reperfusion (I/R) injury in rats in vivo and ex vivo. Male rats were subjected to 30 min ischemia and 2 h reperfusion in the presence or absence of sevoflurane (1.0 minimum alveolar concentration) during the first 15 min of reperfusion. We found that SPC significantly improved hemodynamic performance after reperfusion, alleviated postischemic myocardial infarction, reduced nicotinamide adenine dinucleotide content loss, and cytochrome c release in heart tissues. Furthermore, SPC significantly increased the phosphorylation of endothelial nitric oxide synthase (NOS) and neuronal nitric oxide synthase, and elevated myocardial NOS activity and NO production. All these effects were abolished by treatment with an NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg, i.v.). We also observed myocardial I/R-induced accumulation of autophagosomes in heart tissues, as evidenced by increased ratios of microtubule-associated protein 1 light chain 3 II/I, up-regulation of Beclin 1 and P62, and reduced lysosome-associated membrane protein-2 expression. SPC significantly attenuated I/R-impaired autophagic flux, which were blocked by l-NAME. Moreover, pretreatment with the autophagic flux blocker chloroquine (10 mg/kg, i.p.) increased autophagosome accumulation in SPC-treated heart following I/R and blocked SPC-induced cardioprotection. The same results were also observed in a rat model of myocardial I/R injury ex vivo, suggesting that SPC protects rat hearts against myocardial reperfusion injury by restoring I/R-impaired autophagic flux via an NO-dependent mechanism.
- Published
- 2018
22. Neuroprotective Effects of DTIO, A Novel Analog of Nec-1, in Acute and Chronic Stages After Ischemic Stroke
- Author
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Yong-Ming Zhu, Guizhen Ao, Chen Wang, Xue Gao, Jin Liu, Bo Lin, Shigang Qiao, Wei Li, Yong Ni, Jie-Ru Chen, Huan-Qiu Li, and Hui-Ling Zhang
- Subjects
0301 basic medicine ,Male ,Indoles ,Necroptosis ,Ischemia ,Inflammation ,Pharmacology ,Neuroprotection ,Glial scar ,Proinflammatory cytokine ,Brain Ischemia ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Neurons ,Mice, Inbred ICR ,business.industry ,General Neuroscience ,Imidazoles ,Recovery of Function ,medicine.disease ,Protein Structure, Tertiary ,Stroke ,030104 developmental biology ,medicine.anatomical_structure ,Neuroprotective Agents ,Astrocytes ,Receptor-Interacting Protein Serine-Threonine Kinases ,Chronic Disease ,medicine.symptom ,Inflammation Mediators ,business ,030217 neurology & neurosurgery ,Astrocyte ,Signal Transduction - Abstract
Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3',5'-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn't have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.
- Published
- 2018
23. DPP-4 Inhibitor Sitagliptin Improves Cardiac Function and Glucose Homeostasis and Ameliorates β-Cell Dysfunction Together with Reducing S6K1 Activation and IRS-1 and IRS-2 Degradation in Obesity Female Mice
- Author
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Chen Wang, Hua Li, Huiling Zhang, Jianzhong An, Shigang Qiao, Zhimin Ma, Lei Hong, and Guofang Mao
- Subjects
Cardiac function curve ,medicine.medical_specialty ,lcsh:RC648-665 ,Article Subject ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,030209 endocrinology & metabolism ,P70-S6 Kinase 1 ,030204 cardiovascular system & hematology ,Carbohydrate metabolism ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Sitagliptin ,Internal medicine ,Medicine ,Glucose homeostasis ,business ,Dipeptidyl peptidase-4 ,Homeostasis ,medicine.drug - Abstract
Background. Chronic overnutrition leads to cardiac dysfunction and insulin (INS) resistance. Dipeptidyl peptidase-4 (DPP-4) improves glucose metabolism and insulin sensitivity in both human and animal models. In this study, we explored whether DPP-4 inhibitor sitagliptin (SIT) is involved in the protection of cardiac function and β-cell function using an obesity female mouse model. Methods. Six-week-old C57BL6/J mice were fed a high fat and fructose Western diet with DPP-4 inhibitor SIT for 12 weeks. Cardiac function was examined by echocardiography. Body weight, plasma glucose, and insulin concentrations were measured. The contents of total S6 kinase 1 (S6K1), phosphorylation of S6K1 activation, and INS docking proteins INS receptor substrates 1 and 2 (IRS-1, IRS-2) were assayed, and histology of heart tissue was performed. Results. Chronic Western diet consumption elevated plasma glucose and insulin and caused obesity, diastolic dysfunction, and β-cell dysfunction. DPP-4 inhibition with SIT resulted in reduction in body weight, fasting glucose, and plasma insulin, and improved cardiac diastolic dysfunction. SIT also decreased mTOR/S6K1 activation and prevented the degradation of IRS-1 and IRS-2. Conclusions. This study revealed pleiotropic protective effects of DPP-4 inhibitor SIT on cardiac function, glycemia, and β-cell function together with reducing S6K1 activation and IRS-1 and IRS-2 degradation in the obesity female mouse model.
- Published
- 2018
24. Failure of isoflurane cardiac preconditioning in obese type 2 diabetic mice involves aberrant regulation of microRNA-21, endothelial nitric oxide synthase, and mitochondrial complex I
- Author
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J.R. Kersten, Zhi-Dong Ge, Yingchuan Li, Mingyu Liang, Shigang Qiao, Xiaowen Bai, D. C. Warltier, and Zeljko J. Bosnjak
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Endothelium ,Nitric Oxide Synthase Type III ,Ischemia ,030204 cardiovascular system & hematology ,Nicotinamide adenine dinucleotide ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Reperfusion therapy ,Organ Culture Techniques ,Internal medicine ,medicine ,Animals ,Obesity ,Treatment Failure ,Mice, Knockout ,Electron Transport Complex I ,biology ,Isoflurane ,business.industry ,medicine.disease ,Nitric oxide synthase ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Ischemic Preconditioning, Myocardial ,biology.protein ,Ischemic preconditioning ,business ,Reperfusion injury ,medicine.drug - Abstract
BackgroundDiabetes impairs the cardioprotective effect of volatile anesthetics, yet the mechanisms are still murky. We examined the regulatory effect of isoflurane on microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I in type 2 diabetic mice.MethodsMyocardial ischemia/reperfusion injury was produced in obese type 2 diabetic (db/db) and C57BL/6 control mice ex vivo in the presence or absence of isoflurane administered before ischemia. Cardiac microRNA-21 was quantified by real-time quantitative reverse transcriptional–polymerase chain reaction. The dimers and monomers of endothelial nitric-oxide synthase were measured by Western blot analysis. Mitochondrial nicotinamide adenine dinucleotide fluorescence was determined in Langendorff-perfused hearts.ResultsBody weight and fasting blood glucose were greater in db/db than C57BL/6 mice. Isoflurane decreased left ventricular end-diastolic pressure from 35 ± 8 mmHg in control to 23 ± 9 mmHg (P = 0.019, n = 8 mice/group, mean ± SD) and elevated ±dP/dt 2 h after post-ischemic reperfusion in C57BL/6 mice. These beneficial effects of isoflurane were lost in db/db mice. Isoflurane elevated microRNA-21 and the ratio of endothelial nitric-oxide synthase dimers/monomers and decreased mitochondrial nicotinamide adenine dinucleotide levels 5 min after ischemia in C57BL/6 but not db/db mice. MicroRNA-21 knockout blocked these favorable effects of isoflurane, whereas endothelial nitric-oxide synthase knockout had no effect on the expression of microRNA-21 but blocked the inhibitory effect of isoflurane preconditioning on nicotinamide adenine dinucleotide.ConclusionsFailure of isoflurane cardiac preconditioning in obese type 2 diabetic db/db mice is associated with aberrant regulation of microRNA-21, endothelial nitric-oxide synthase, and mitochondrial respiratory complex I.
- Published
- 2018
25. Propofol Induces Apoptosis of Neurons but Not Astrocytes, Oligodendrocytes, or Neural Stem Cells in the Neonatal Mouse Hippocampus
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Congshan Jiang, Sarah Logan, Thiago Arzua, Yasheng Yan, Shigang Qiao, Chika Kikuchi, Xiaowen Bai, and Ivan Zaja
- Subjects
0301 basic medicine ,Hippocampus ,neurons ,oligodendrocytes ,Biology ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,medicine ,selective vulnerability ,Apoptosis Marker ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,neural stem cells ,propofol ,General Neuroscience ,apoptosis ,astrocytes ,Neural stem cell ,Oligodendrocyte ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Apoptosis ,Cerebral cortex ,Neuron ,Neuroscience ,030217 neurology & neurosurgery ,Astrocyte - Abstract
It has been shown that propofol can induce widespread apoptosis in neonatal mouse brains followed by long-term cognitive dysfunction. However, selective brain area and cell vulnerability to propofol remains unknown. This study was aimed to dissect toxic effect of propofol on multiple brain cells, including neurons, astrocytes, oligodendrocytes, and neural stem cells (NSCs). Seven-day-old mice were intraperitoneally administrated propofol or intralipid as a vehicle control for 6 hours. To identify vulnerable cells undergoing apoptosis following propofol exposure, brain sagittal sections were co-stained with antibodies against an apoptosis marker along with neuron, astrocyte, oligodendrocyte, or NSC markers using immunofluorescence staining. The results showed widespread apoptosis in propofol-treated brains (apoptotic cells: 1.55 ± 0.04% and 0.06 ± 0.01% in propofol group and intralipid-treated control group, respectively). Apoptotic cell distribution exhibits region- and cell-specific patterns. Several brain regions (e.g., cerebral cortex and hippocampus) were more vulnerable to propofol than other brain regions. Most apoptotic cells in the hippocampus were located in the cornus ammonis 1 (CA1) subfield. These apoptotic cells were only detected in neurons and not astrocytes, oligodendrocytes, or NSCs. These data demonstrate that different brain regions, subfields, and different types of neuronal cells in mice exhibit various vulnerabilities to propofol. Understanding region- and cell-specific susceptibility to propofol will help to better understand cellular contribution to developmental neurotoxicity and further develop novel therapeutic targets.
- Published
- 2017
26. Inhibition of PKCβ2 overexpression ameliorates myocardial ischaemia/reperfusion injury in diabetic rats via restoring caveolin-3/Akt signaling
- Author
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Song-Yan Liao, Gordon Tin Chun Wong, Shaoqing Lei, Zhengyuan Xia, Haobo Li, Zhi-Dong Ge, Yanan Liu, Jiqin Jin, Shigang Qiao, and Michael G. Irwin
- Subjects
Cardiac function curve ,medicine.medical_specialty ,TUNEL assay ,business.industry ,Ischemia ,General Medicine ,medicine.disease ,Ruboxistaurin ,Caveolin 3 ,chemistry.chemical_compound ,Endocrinology ,Biochemistry ,chemistry ,Internal medicine ,cardiovascular system ,Phosphorylation ,Medicine ,business ,Protein kinase B ,Reperfusion injury - Abstract
Activation of PKCβ (protein kinase Cβ) plays a critical role in myocardial I/R (ischaemia/reperfusion) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 overexpression is associated with increased vulnerability to post-ischaemic I/R injury with concomitantly impaired cardiomyocyte Cav (caveolin)-3 and Akt signalling compared with non-diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signalling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxistaurin (RBX, 1 mg/kg per day) for 4 weeks, starting from 1 week after diabetes induction, before inducing myocardial I/R achieved by occluding the left descending coronary artery followed by reperfusion. Cardiac function was measured using a pressure–volume conductance system. In an in vitro study, cardiac H9C2 cells were exposed to high glucose (30 mmol/l) and subjected to hypoxia followed by reoxygenation (H/R) in the presence or absence of the selective PKCβ2 inhibitor CGP53353 (1 μmol/l), siRNAs of PKCβ2 or Cav-3 or Akt. Cell apoptosis and mitochondrial membrane potential were assessed by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) and JC-1 staining respectively. RBX significantly decreased post-ischaemic myocardial infarct size (35±5% compared with 49±3% in control, P
- Published
- 2015
27. Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling
- Author
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Zhi-Dong Ge, David C. Warltier, Zhengyuan Xia, Yanan Liu, Shigang Qiao, Shelley L. Baumgardt, Judy R. Kersten, Juan Fang, Yang Shi, Jeannette Vasquez-Vivar, and Zeljko J. Bosnjak
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Science ,Myocardial Infarction ,Infarction ,Gene Expression ,Nitric Oxide Synthase Type I ,030204 cardiovascular system & hematology ,Ryanodine receptor 2 ,Article ,Contractility ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Myocyte ,Animals ,Myocytes, Cardiac ,Transgenes ,Phosphorylation ,Protein kinase A ,GTP Cyclohydrolase ,Multidisciplinary ,biology ,Ventricular Remodeling ,business.industry ,Endoplasmic reticulum ,Tetrahydrobiopterin ,medicine.disease ,Fibrosis ,3. Good health ,Nitric oxide synthase ,Sarcoplasmic Reticulum ,030104 developmental biology ,Endocrinology ,Organ Specificity ,Heart Function Tests ,biology.protein ,cardiovascular system ,Medicine ,Calcium ,business ,medicine.drug - Abstract
GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction.
- Published
- 2017
28. N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes
- Author
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Junwen Wang, Shaoqing Lei, Kwok F. J. Ng, Tingting Wang, Aimin Xu, Zipeng Liu, Michael G. Irwin, Xiaowen Mao, Gordon Tin Chun Wong, Zhengyuan Xia, Paul M. Vanhoutte, Shigang Qiao, and Haobo Li
- Subjects
Male ,STAT3 Transcription Factor ,medicine.medical_specialty ,Allopurinol ,Myocardial Reperfusion Injury ,Nitric Oxide ,Biochemistry ,Diabetes Mellitus, Experimental ,Nitric oxide ,Diabetes Complications ,Wortmannin ,Acetylcysteine ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Phosphorylation ,STAT3 ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Janus Kinases ,biology ,Adiponectin ,business.industry ,Rats ,Up-Regulation ,Endocrinology ,Gene Expression Regulation ,chemistry ,biology.protein ,business ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,medicine.drug - Abstract
N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.
- Published
- 2013
29. Delayed anesthetic preconditioning protects against myocardial infarction via activation of nuclear factor-κB and upregulation of autophagy
- Author
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Xuemei Wu, Chen Wang, Hong Liu, Chunfeng Liu, Hong Xie, and Shigang Qiao
- Subjects
Male ,Methyl Ethers ,Blotting, Western ,Myocardial Infarction ,Infarction ,Apoptosis ,Myocardial Reperfusion Injury ,Cathepsin B ,Rats, Sprague-Dawley ,Sevoflurane ,chemistry.chemical_compound ,Microscopy, Electron, Transmission ,Downregulation and upregulation ,Phagosomes ,Autophagy ,medicine ,Animals ,Parthenolide ,Inflammation ,Cardioprotection ,Analysis of Variance ,business.industry ,Myocardium ,Hemodynamics ,NF-kappa B ,medicine.disease ,Rats ,Up-Regulation ,Anesthesiology and Pain Medicine ,chemistry ,Anesthesia ,Anesthetics, Inhalation ,Ischemic Preconditioning, Myocardial ,Ischemic preconditioning ,Anesthesia, Inhalation ,business ,Biomarkers - Abstract
Delayed volatile anesthetic preconditioning (APC) can protect against myocardial ischemia/reperfusion (I/R) injury; the delayed phase is called the second window of protection (SWOP), but the underlying mechanism is unclear. Nuclear factor-κB (NF-κB) is involved in the myocardial protection conferred by APC in the acute phase; autophagy has been reported to confer apoptosis inhibition and infarction reduction. We hypothesized that APC initiates delayed cardioprotection against I/R injury via the activation of NF-kB and upregulation of autophagy, thus attenuating the inflammatory response and apoptosis After a rat I/R model was set up, left ventricular samples were obtained before I/R to assess NF-κB-DNA binding activity and microtubule-associated protein 1 light chain 3 (LC3) and cathepsin B protein expression, and to examine autophagosomes with a transmission electron microscope. Infarct size and the expressions of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and caspase-3 were measured at the end of 2-h reperfusion. The infarct size was significantly reduced in the SWOP group (30 ± 3 %) when compared with that in the I/R group (47 ± 7 %, P
- Published
- 2012
30. Cardiomyocyte GTP Cyclohydrolase 1 Protects the Heart Against Diabetic Cardiomyopathy
- Author
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Shelley L. Baumgardt, David C. Warltier, Zhi-Dong Ge, Jianhai Du, Shigang Qiao, Yanan Liu, Juan Fang, Zeljko J. Bosnjak, Judy R. Kersten, Hsiang En Wu, Yang Shi, and Mark Paterson
- Subjects
0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Diabetic Cardiomyopathies ,Leupeptins ,Blood Pressure ,Mice, Transgenic ,Nitric Oxide Synthase Type I ,030204 cardiovascular system & hematology ,p38 Mitogen-Activated Protein Kinases ,Article ,Streptozocin ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Diabetic cardiomyopathy ,medicine ,Myocyte ,Animals ,Myocytes, Cardiac ,Calcium Signaling ,GTP Cyclohydrolase ,Multidisciplinary ,Ventricular Remodeling ,business.industry ,Endoplasmic reticulum ,Myocardium ,Hemodynamics ,Tetrahydrobiopterin ,Streptozotocin ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Heart failure ,Hypoxanthines ,business ,medicine.drug - Abstract
Diabetic cardiomyopathy increases the risk of heart failure and death. At present, there are no effective approaches to preventing its development in the clinic. Here we report that reduction of cardiac GTP cyclohydrolase 1 (GCH1) degradation by genetic and pharmacological approaches protects the heart against diabetic cardiomyopathy. Diabetic cardiomyopathy was induced in C57BL/6 wild-type mice and transgenic mice with cardiomyocyte-specific overexpression of GCH1 with streptozotocin and control animals were given citrate buffer. We found that diabetes-induced degradation of cardiac GCH1 proteins contributed to adverse cardiac remodeling and dysfunction in C57BL/6 mice, concomitant with decreases in tetrahydrobiopterin, dimeric and phosphorylated neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ handling proteins, intracellular [Ca2+]i and sarcoplasmic reticulum Ca2+ content and increases in phosphorylated p-38 mitogen-activated protein kinase and superoxide production. Interestingly, GCH-1 overexpression abrogated these detrimental effects of diabetes. Furthermore, we found that MG 132, an inhibitor for 26S proteasome, preserved cardiac GCH1 proteins and ameliorated cardiac remodeling and dysfunction during diabetes. This study deepens our understanding of impaired cardiac function in diabetes, identifies GCH1 as a modulator of cardiac remodeling and function and reveals a new therapeutic target for diabetic cardiomyopathy.
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- 2016
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31. Parthenolide attenuates LPS-induced activation of NF-κB in a time-dependent manner in rat myocardium
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Shigang Qiao, Xuemei Wu, Xia Liu, Hong Xie, Chen Wang, Hong Liu, and Chunfeng Liu
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P50 ,Lipopolysaccharide ,Dependent manner ,parthenolide ,business.industry ,nuclear-factor-kappa B ,Medical Biotechnology ,lipopolysaccharide ,NF-κB ,General Medicine ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,nuclear-factor-κB ,chemistry.chemical_compound ,IκBα ,chemistry ,5.1 Pharmaceuticals ,In vivo ,myocardium ,Medicine ,Rat myocardium ,Parthenolide ,Development of treatments and therapeutic interventions ,business ,Research Paper - Abstract
Parthenolide (PTN), a selective nuclear factor kappa B (NF-κB) inhibitor, has been used extensively to inhibit NF-κB activation. The duration of the inhibitory effect of PTN on NF-κB in vivo remains unclear. This study was to determine whether a lipopolysaccharide (LPS) challenge 6, 12 and 24 h after the administration of PTN could activate NF-κB. Rats were devided into five groups. The rats in the PTN, PTN+LPS and DMSO groups were injected intraperitoneally with PTN or DMSO. After 6, 12 or 24 h, LPS was administered in LPS and PTN+LPS groups. The expressions of NF-κB p50, IκBα and p-IκBα were inhibited in both PTN and PTN+LPS group at end of 6 and 12 h and no effects at 24 h. In summary, myocardial NF-κB expression occurs 1 h after the administration of LPS. PTN blocks this effect given at 6 h and no inhibitory effect 24 h after administration in vivo.
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- 2012
32. Remifentanil Preconditioning Reduces Postischemic Myocardial Infarction and Improves Left Ventricular Performance via Activation of the Janus Activated Kinase-2/Signal Transducers and Activators of Transcription-3 Signal Pathway and Subsequent Inhibition of Glycogen Synthase Kinase-3β in Rats
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Tingting Wang, Shaoqing Lei, Yanan Liu, Gordon Tin Chun Wong, Xiaowen Mao, Zhengyuan Xia, Shigang Qiao, Yan Wang, Michael G. Irwin, and Chi Wai Cheung
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0301 basic medicine ,Male ,STAT3 Transcription Factor ,Myocardial Infarction ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,Ventricular Function, Left ,Rats, Sprague-Dawley ,Remifentanil ,03 medical and health sciences ,Glycogen Synthase Kinase 3 ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Piperidines ,GSK-3 ,Medicine ,Animals ,Myocytes, Cardiac ,Phosphorylation ,STAT3 ,Ischemic Preconditioning ,GSK3B ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Janus kinase 2 ,Glycogen Synthase Kinase 3 beta ,biology ,business.industry ,Janus Kinase 2 ,Cell biology ,Rats ,030104 developmental biology ,Anesthesia ,biology.protein ,Ischemic preconditioning ,Signal transduction ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Remifentanil preconditioning attenuates myocardial ischemia reperfusion injury, but the underlying mechanism is incompletely understood. The Janus activated kinase-2 (JAK2)/signal transducers and activators of transcription-3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways are critical in both ischemic and pharmacologic preconditioning cardioprotection, which involve the inactivation of glycogen synthase kinase-3β. We hypothesized that remifentanil preconditioning confers cardioprotection via the JAK2/STAT3 and/or PI3K/Akt activation-mediated glycogen synthase kinase-3β inhibition.Pharmacologic intervention.Research laboratory.Male Sprague-Dawley rats.In vivo and in vitro treatments.Male Sprague-Dawley rats (n = 6 per group) were sham operated or subjected to myocardial ischemia reperfusion injury. The JAK2 inhibitor AG490 (3 mg/kg), the PI3K inhibitor wortmannin (15 μg/kg), or the glycogen synthase kinase-3β inhibitor SB216763 (600 μg/kg) were given before inducing in vivo myocardial ischemia reperfusion injury achieved by occluding coronary artery for 30 minutes followed by 120 minutes of reperfusion in the absence or presence of remifentanil preconditioning (6 μg/kg/min). Also, isolated rat hearts were Langendorff perfused and subjected to 30 minutes of global ischemia and 120 minutes of reperfusion without or with remifentanil preconditioning (100 ng/mL) in the presence or absence of AG490 and/or SB216763. Isolated rat cardiomyocytes and H9C2 cells were subjected to hypoxia/reoxygenation alone or in combination with AG490 (100 μM), wortmannin (100 nM), or SB216763 (3 μM) without or with remifentanil preconditioning (2.5 μM). Remifentanil preconditioning reduced postischemic myocardial infarction and hemodynamic dysfunction induced by myocardial ischemia reperfusion injury concomitant with increased phosphorylation of STAT3 at tyr-705 (p-STAT3) and glycogen synthase kinase-3β but not Akt. AG490 but not wortmannin cancelled remifentanil preconditioning cardioprotection, and SB216763 restored it despite the presence of AG490. In Langendorff-perfused hearts, AG490-mediated cancellation of remifentanil preconditioning cardioprotection in attenuating postischemic myocardial infarction and creatinine kinase-MB release was reverted by concomitant administration of SB216763. Remifentanil preconditioning also attenuated posthypoxic cardiomyocyte injury and increased p-STAT3 and glycogen synthase kinase-3β in isolated primary cardiomyocytes and H9C2 cells. STAT3 gene knockdown with specific synthetic RNA cancelled remifentanil preconditioning cardioprotection, whereas glycogen synthase kinase-3β gene knockdown, which per se did not affect STAT3 under hypoxia/reoxygenation condition, preserved remifentanil preconditioning cardioprotection regardless of STAT3 abrogation.Remifentanil preconditioning confers cardioprotection primarily via activation of JAK2/STAT3 signaling that can function independent of PI3K/Akt activation. Glycogen synthase kinase-3β is a critical downstream effector of remifentanil preconditioning cardioprotection.
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- 2015
33. Abstracts of Posters presented at the 2011 Annual Meeting of the International Anesthesia Research Society Vancouver, British Columbia, Canada May 21-24, 2011
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Gtc Wong, Y Liu, Zhiping Xia, H Liu, M. G. Irwin, and Shigang Qiao
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Anesthesiology and Pain Medicine ,Adiponectin ,business.industry ,Anesthesia ,Myocardial Reperfusion Injury ,Medicine ,Allopurinol ,Pharmacology ,business ,Streptozotocin ,medicine.drug - Abstract
This journal suppl. contain Abstracts of Posters presented at the 2011 Annual Meeting of the International Anesthesia Research Society
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- 2011
34. MicroRNA-21 Mediates Isoflurane-induced Cardioprotection against Ischemia-Reperfusion Injury via Akt/Nitric Oxide Synthase/Mitochondrial Permeability Transition Pore Pathway
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Ivan Zaja, David C. Warltier, Matthias L. Riess, Zhi-Dong Ge, Zeljko J. Bosnjak, Judy R. Kersten, Jessica Olson, Yasheng Yan, Yanan Liu, Mark Paterson, Shigang Qiao, and Mingyu Liang
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Male ,Cardiotonic Agents ,Ischemia ,Myocardial Reperfusion Injury ,Mitochondrion ,Mitochondrial Membrane Transport Proteins ,Mice ,Organ Culture Techniques ,medicine ,Animals ,Myocytes, Cardiac ,Protein kinase B ,Cells, Cultured ,Cardioprotection ,Mice, Knockout ,biology ,Isoflurane ,business.industry ,Mitochondrial Permeability Transition Pore ,medicine.disease ,Cell biology ,Nitric oxide synthase ,Mice, Inbred C57BL ,MicroRNAs ,Anesthesiology and Pain Medicine ,Mitochondrial permeability transition pore ,Anesthesia ,Knockout mouse ,biology.protein ,Nitric Oxide Synthase ,business ,Reperfusion injury ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Background: The role of microRNA-21 in isoflurane-induced cardioprotection is unknown. The authors addressed this issue by using microRNA-21 knockout mice and explored the underlying mechanisms. Methods: C57BL/6 and microRNA-21 knockout mice were echocardiographically examined. Mouse hearts underwent 30 min of ischemia followed by 2 h of reperfusion in vivo or ex vivo in the presence or absence of 1.0 minimum alveolar concentration of isoflurane administered before ischemia. Cardiac Akt, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) proteins were determined by Western blot analysis. Opening of the mitochondrial permeability transition pore (mPTP) in cardiomyocytes was induced by photoexcitation-generated oxidative stress and detected by rapid dissipation of tetramethylrhodamine ethyl ester fluorescence using a confocal microscope. Results: Genetic disruption of miR-21 gene did not alter phenotype of the left ventricle, baseline cardiac function, area at risk, and the ratios of phosphorylated-Akt/Akt, phosphorylated-eNOS/eNOS, and phosphorylated-nNOS/nNOS. Isoflurane decreased infarct size from 54 ± 10% in control to 36 ± 10% (P < 0.05, n = 8 mice per group), improved cardiac function after reperfusion, and increased the ratios of phosphorylated-Akt/AKT, phosphorylated-eNOS/eNOS, and phosphorylated-nNOS/nNOS in C57BL/6 mice subjected to ischemia–reperfusion injury. These beneficial effects of isoflurane were lost in microRNA-21 knockout mice. There were no significant differences in time of the mPTP opening induced by photoexcitation-generated oxidative stress in cardiomyocytes isolated between C57BL/6 and microRNA-21 knockout mice. Isoflurane significantly delayed mPTP opening in cardiomyocytes from C57BL/6 but not from microRNA-21 knockout mice. Conclusions: Isoflurane protects mouse hearts from ischemia–reperfusion injury by a microRNA-21-dependent mechanism. The Akt/NOS/mPTP pathway is involved in the microRNA-21-mediated protective effect of isoflurane.
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- 2015
35. Role of mitochondrial ATP-sensitive potassium channel-mediated PKC-ε in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats
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Hong Xie, Hong Liu, Chunfeng Liu, Chao Wang, Sumei Hu, and Shigang Qiao
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Male ,Medicine (General) ,Potassium Channels ,Time Factors ,Physiology ,Pharmacology ,Biochemistry ,Medical and Health Sciences ,Rats, Sprague-Dawley ,Random Allocation ,Ischemia ,Troponin I ,General Pharmacology, Toxicology and Pharmaceutics ,Biology (General) ,Ischemic Preconditioning ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Caspase 8 ,Blotting ,General Neuroscience ,Heart ,General Medicine ,Anesthesia ,Ischemic Preconditioning, Myocardial ,lcsh:Medicine (General) ,Anti-Arrhythmia Agents ,Western ,medicine.drug ,Cardiac function curve ,Methyl Ethers ,ATP-sensitive potassium channel ,QH301-705.5 ,Immunology ,Blotting, Western ,Biophysics ,mitoK(atp) channel ,Ocean Engineering ,Myocardial Reperfusion Injury ,Preconditioning ,Protective Agents ,Sevoflurane ,R5-920 ,Protein kinase C ,medicine ,Animals ,Myocardial ,Neurology & Neurosurgery ,business.industry ,Hemodynamics ,Biomedical Sciences ,Reproducibility of Results ,Cell Biology ,medicine.disease ,mitoKatp channel ,Rats ,lcsh:Biology (General) ,Coronary occlusion ,Reperfusion ,Ischemic preconditioning ,Sprague-Dawley ,business ,Hydroxy Acids ,Reperfusion injury ,Decanoic Acids ,Platelet Aggregation Inhibitors - Abstract
©. 2015 Associacao Brasileira de Divulgacao Cientifica. This study aimed to determine the role of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels and protein kinase C (PKC)-ε in the delayed protective effects of sevoflurane preconditioning using Langendorff isolated heart perfusion models. Fifty-four isolated perfused rat hearts were randomly divided into 6 groups (n=9). The rats were exposed for 60 min to 2.5% sevoflurane (the second window of protection group, SWOP group) or 33% oxygen inhalation (I/R group) 24 h before coronary occlusion. The control group (CON) and the sevoflurane group (SEVO) group were exposed to 33% oxygen and 2.5% sevoflurane for 60 min, respectively, without coronary occlusion. The mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) was given 30 min before sevoflurane preconditioning (5-HD+SWOP group). Cardiac function indices, infarct sizes, serum cardiac troponin I (cTnI) concentrations, and the expression levels of phosphorylated PKC-ε (p-PKC-ε) and caspase-8 were measured. Cardiac function was unchanged, p-PKC-ε expression was upregulated, caspase-8 expression was downregulated, cTnI concentrations were decreased, and the infarcts were significantly smaller (P,0.05) in the SWOP group compared with the I/R group. Cardiac function was worse, p-PKC-ε expression was downregulated, caspase-8 expression was upregulated, cTnI concentration was increased and infarcts were larger in the 5-HD+SWOP group (P,0.05) compared with the SWOP group. The results suggest that mitoKATP channels are involved in the myocardial protective effects of sevoflurane in preconditioning against I/R injury, by regulating PKC-ε phosphorylation before ischemia, and by downregulating caspase-8 during reperfusion.
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- 2015
36. Sevoflurane post-conditioning reduces rat myocardial ischemia reperfusion injury through an increase in NOS and a decrease in phopshorylated NHE1 levels
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Jiang Zhu, Jianfang Cao, Ying Sun, Chen Wang, Hong Xie, Qin Shao, Shigang Qiao, Haorong Wu, and Ming Ying
- Subjects
Male ,Cell ,Myocardial Infarction ,Pharmacology ,Mitochondrial Membrane Transport Proteins ,Rats, Sprague-Dawley ,Phagosomes ,Enzyme Inhibitors ,Phosphorylation ,myocardial ischemia/reperfusion ,Ischemic Postconditioning ,Sodium-Hydrogen Exchanger 1 ,Caspase 3 ,Reverse Transcriptase Polymerase Chain Reaction ,apoptosis ,Heart ,Articles ,General Medicine ,Cell cycle ,medicine.anatomical_structure ,NG-Nitroarginine Methyl Ester ,Anesthetics, Inhalation ,NOS/p-NHE1 ,Corrigendum ,Microtubule-Associated Proteins ,medicine.drug ,Methyl Ethers ,Cardiotonic Agents ,Sodium-Hydrogen Exchangers ,Blotting, Western ,Myocardial Reperfusion Injury ,In Vitro Techniques ,Sevoflurane ,Microscopy, Electron, Transmission ,Genetics ,medicine ,Autophagy ,Animals ,Oncogene ,business.industry ,Mitochondrial Permeability Transition Pore ,Myocardium ,Cancer ,medicine.disease ,Molecular medicine ,sevoflurane post-conditioning ,Apoptosis ,Nitric Oxide Synthase ,business ,Reperfusion injury - Abstract
The protective effects of sevoflurane post-conditioning against myocardial ischemia/reperfusion (I/R) injury (MIRI) have been previously reported. However, the mechanisms responsible for these protective effects remain elusive. In this study, in order to investigate the molecular mechanisms responsible for the protective effects of sevoflurane post-conditioning on isolated rat hearts subjected to MIRI, Sprague-Dawley rat hearts were randomly divided into the following 6 groups: i) the sham-operated control; ii) 2.5% sevoflurane; iii) ischemia/reperfusion (I/R); iv) 2.5% sevoflurane post-conditioning plus I/R; v) 2.5% sevoflurane post-conditioning + NG-nitro-L-arginine methyl ester (L-NAME) plus I/R; and vi) L-NAME plus I/R. The infarct size was measured using 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Additionally, the myocardial nitric oxide (NO), NO synthase (NOS) and nicotinamide adenine dinucleotide (NAD+) levels were determined. Autophagosomes and apoptosomes in the myocardium were detected by transmission electron microscopy. The levels of Bcl-2, cleaved caspase-3, Beclin-1, microtubule-associated protein light chain 3 (LC3)-I/II, Na+/H+ exchanger 1 (NHE1) and phosphorylated NHE1 protein were measured by western blot analysis. NHE1 mRNA levels were measured by reverse transcription-quantitative polymerase chain reaction. Compared with the I/R group, 15 min of exposure to 2.5% sevoflurane during early reperfusion significantly decreased the myocardial infarct size, the autophagic vacuole numbers, the NHE1 mRNA and protein expression of cleaved caspase-3, Beclin-1 and LC3-I/II. Post-conditioning with 2.5% sevoflurane also increased the NO and NOS levels and Bcl-2 protein expression (P
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- 2015
37. Antioxidants N‐Acetylcysteine and Allopurinol attenuation of postischemic myocardial injury in diabetic rats involve Akt and STAT3 mediated eNOS activation
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Zhengyuan Xia, Shaoqing Lei, Tingting Wang, Kwok F. J. Ng, Xiaowen Mao, Shigang Qiao, and Michael G. Irwin
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medicine.medical_specialty ,biology ,business.industry ,Allopurinol ,biology.organism_classification ,Biochemistry ,Acetylcysteine ,Endocrinology ,Enos ,Internal medicine ,Genetics ,medicine ,biology.protein ,business ,STAT3 ,Molecular Biology ,Protein kinase B ,Biotechnology ,medicine.drug - Published
- 2012
38. Remifentanil preconditioning confers cardioprotection via the JAK/STAT but not PI3K/Akt pathway in rats
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Tingting Wang, Zhengyuan Xia, Gordon Tin Chun Wong, Shigang Qiao, Yanan Liu, Xiaowen Mao, and Michael G. Irwin
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Cardioprotection ,Genetics ,Remifentanil ,medicine ,JAK-STAT signaling pathway ,Pharmacology ,Molecular Biology ,Biochemistry ,PI3K/AKT/mTOR pathway ,Biotechnology ,medicine.drug - Published
- 2011
39. N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats
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Zhengyuan Xia, Shaoqing Lei, Michael G. Irwin, Shigang Qiao, Tingting Wang, Yanan Liu, Kwok F. J. Ng, Karen S.L. Lam, and Aimin Xu
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Blood Glucose ,Male ,Myocardial Infarction ,lcsh:Medicine ,Isoprostanes ,medicine.disease_cause ,Dinoprost ,Cardiovascular ,Antioxidants ,Acetylcysteine ,Rats, Sprague-Dawley ,Endocrinology ,Enos ,Creatine Kinase, MB Form ,Myocardial infarction ,lcsh:Science ,Multidisciplinary ,biology ,Drug Synergism ,Animal Models ,Allopurinol - pharmacology - therapeutic use ,Cytokines ,Medicine ,Antioxidants - pharmacology - therapeutic use ,Adiponectin ,Receptors, Adiponectin ,medicine.drug ,Signal Transduction ,Research Article ,medicine.medical_specialty ,Allopurinol ,Immunology ,Myocardial Reperfusion Injury ,Diabetes Complications ,Model Organisms ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Acetylcysteine - pharmacology - therapeutic use ,Diabetes Complications - drug therapy - metabolism - pathology - physiopathology ,Protein kinase B ,Biology ,Diabetic Endocrinology ,business.industry ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Myocardium ,lcsh:R ,Hemodynamics ,medicine.disease ,Streptozotocin ,biology.organism_classification ,Rats ,Oxidative Stress ,Gene Expression Regulation ,Immune System ,Adiponectin - biosynthesis - metabolism ,Rat ,lcsh:Q ,business ,Oxidative stress ,Biomarkers - Abstract
Background: Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes. Methodology/Principal Findings: Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-α (all P, published_or_final_version
- Published
- 2011
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