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Doxorubicin (DOX) is an important chemotherapeutic agent for the treatment of hematologic tumors and breast carcinoma. However, its clinical application is limited owing to severe cardiotoxicity. Pyroptosis is a form of programmed cell death linked to DOX-induced cardiotoxicity. Bone mesenchymal stem cell–derived exosomes (BMSC-Exos) and endothelial progenitor cells-derived exosomes(EPC-Exos) have a protective role in the myocardium. Here we found that BMSC-Exos could improve DOX-induced cardiotoxicity by inhibiting pyroptosis, but EPC-Exos couldn’t. Compared with EPCs-Exo, BMSC-Exo-overexpressing lncRNA GHET1 more effectively suppressed pyroptosis, protecting against DOX-induced cardiotoxicity. Further studies showed that lncRNA GHET1 effectively decreased the expression of Nod-like receptorprotein 3 (NLRP3), which plays a vital role in pyroptosis by binding to IGF2 mRNA-binding protein 1 (IGF2BP1), a non-catalytic posttranscriptional enhancer of NLRP3 mRNA. In summary, lncRNA GHET1 released by BMSC-Exo ameliorated DOX-induced pyroptosis by targeting IGF2BP1 to reduce posttranscriptional stabilization of NLRP3.

Objectives. We conducted a meta-analysis to quantitatively evaluate the effect of melatonin therapy on patients with myocardial ischemia-reperfusion injury (MIRI) and explore the influencing factors. Background. Although preclinical studies have shown that melatonin can alleviate MIRI, its protective effect on MIRI in patients remains controversial. Methods. We searched PubMed, the Cochrane Library, and Embase. The primary outcome was cardiac function (left ventricular ejection fraction [LVEF], left ventricular end-diastolic volume [LVEDV], and left ventricular end-systolic volume [LVESV]) and myocardial infarct parameters (total left ventricular mass and infarct size). Results. We included nine randomized controlled clinical trials with 631 subjects. Our results showed that melatonin had no significant effects on the primary outcome, but subgroup analyses indicated that when melatonin was administered by intravenous and intracoronary injection at the early stage of myocardial ischemia, LVEF was improved ( P = 0.03 ) and the infarct size was reduced ( P = 0.01 ), whereas when melatonin was injected at the late stage of myocardial ischemia (≥3.5 h or 2.5 h), the results were the opposite. Furthermore, melatonin intervention reduced the level of cardiac injury markers, inflammatory cytokines, oxidation factors, and increased the level of antioxidant factors ( P < 0.001 ). Conclusions. The results indicated that the cardioprotective function of melatonin for MIRI was influenced by the route and timing regimen of melatonin administration; the mechanism of which may be associated with the production of inflammatory cytokines, the balance of oxidation, and antioxidant factors.

Doxorubicin (DOX) has a wide antitumor spectrum, but its adverse cardiotoxicity may lead to heart failure. Urotensin II (UII) is the most potent vasoconstrictor in mammals. It plays a role by activating the UII receptor (UT), the orphan G protein-coupled receptor (GPR14), collectively referred to as the UII/UT system. In the new version of "Chinese expert consensus on cardiac rehabilitation of chronic heart failure," it is pointed out that exercise rehabilitation is the cornerstone of cardiac rehabilitation. In this study, in vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats. It was found that the UT antagonist Urantide and exercise training improved DOX-induced cardiac insufficiency, reduced DOX-induced cardiomyocyte apoptosis, improved the structural disorder of myocardial fibers, and inhibited DOX-induced myocardial fibrosis. Further studies showed that Urantide alleviated DOX-induced cardiotoxicity by downregulating the expression levels of the p38 mitogen-activated protein kinase signaling pathway.

Significance: Heart failure, a disease with extremely high incidence, is closely associated with inflammation and oxidative stress. The Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway plays an important role in the occurrence and development of heart failure. Recent advances: Previous studies have shown that TLR4/NF-κB causes heart failure by inducing oxidative stress and inflammation; damaging the endothelia; promoting fibrosis; and inducing myocardial hypertrophy, apoptosis, pyroptosis, and autophagy. Critical issues: Understanding the pathogenesis of heart failure is essential for the treatment of this disease. In this review, we outline the mechanisms underlying TLR4/NF-κB pathway-mediated heart failure and discuss drugs that alleviate heart failure by regulating the TLR4/NF-κB pathway. Future directions: During TLR4/NF-κB overactivation, interventions targeting specific receptor antagonists may effectively alleviate heart failure, thus providing a basis for the development of new anti-heart failure drugs.

Doxorubicin (DOX) has a wide antitumor spectrum, but its adverse cardiotoxicity may lead to heart failure. Urotensin II (UⅡ) is the most potent vasoconstrictor in mammals. It plays a role by activating the UII receptor (UT), the orphan G protein-coupled receptor (GPR14), collectively referred to as the UII/UT system. In the new version of "Chinese expert consensus on cardiac rehabilitation of chronic heart failure," it is pointed out that exercise rehabilitation is the cornerstone of cardiac rehabilitation. In this study, in vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats. It was found that the UT antagonist Urantide and exercise training improved DOX-induced cardiac insufficiency, reduced DOX-induced cardiomyocyte apoptosis, improved the structural disorder of myocardial fibers, and inhibited DOX-induced myocardial fibrosis. Further studies showed that Urantide alleviated DOX-induced cardiotoxicity by downregulating the expression levels of the p38 mitogen-activated protein kinase signaling pathway.

Background Increased Hcy level is an independent risk factor for coronary heart disease (CHD). It was proposed that yellow rice wine improves Hcy-induced EPCs dysfunction and inhibits the development of atherosclerotic plaques. In this study, we observed whether yellow rice wine and red wine improve the properties of homocysteine (Hcy)-induced endothelial progenitor cells (EPCs). Methods The bone marrow of rats was extracted to isolate EPCs from the bone marrow cell suspension using density-gradient centrifugation. The cells were inoculated on culture plates coated with human fibronectin (HFN), to induce mononuclear cell differentiation into EPCs. Samples were divided into 5 groups including a control group. Western blotting. and NO assays were used respectively to observe the generation of eNOS, p-eNOS and NO. MTT and transwell assays were conducted. Apoptosis and in vitro angiogenesis of EPCs were determined. Results Compared with the control group, the potential for proliferation, migration and in vitro angiogenesis of EPCs decreased significantly following Hcy intervention (P 0.05). No impact on apoptotic function of EPCs was observed (P > 0.05). Hcy significantly lowers the capacity of proliferation, migration and in vitro angiogenesis of EPCs and reduces the production of eNOS, p-eNOS and NO. Conclusion Our results showed Hcy significantly lowers the capacity of proliferation, migration and in vitro angiogenesis of EPCs and reduces the production of eNOS, p-eNOS and NO,which indicates that yellow rice wine and red wine in small doses improve the functions of EPCs.

PurposeDiabetic heart failure (DHF) or cardiomyopathy is a common complication of diabetes; however, the underlying mechanism is not clear. In the present study, the authors searched for differentially expressed genes associated with DHF and the molecular types of immune cells based on bioinformatics.MethodsThe RNA expression dataset of DHF was obtained from the NCBI Gene Expression Omnibus (GEO) database. After preprocessing the data, the differentially expressed genes (DEGs) between the DHF group and the non-diabetic heart failure (NHF) group were screened and intersected with immune-related genes (IRGs) in the ImmPort database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID tool. The ssGSEA algorithm was used to evaluate immune infiltration of the heart tissue in each group. In addition, the protein-protein interaction (PPI) network and miRNA-mRNA network were constructed using the STRING online website and Cytoscape program. Finally, validation analysis was performed using animal models.ResultsEight immune-related core genes were identified. GO and KEGG showed that core genes were mainly enriched in angiogenesis and cytokine-cytokine receptor interaction. Immune infiltration results showed that activated dendritic cells, central memory CD4 T cells, central memory CD8 T cells, myeloid-derived suppressor cells (MDSCs), neutrophils, and regulatory T cells may be involved in DHF. Neutrophils may play a key role in the pathogenesis of HF in diabetes.ConclusionImmune-related core genes and immune infiltrating cells provide a new perspective on the pathogenesis of DHF.

Objectives: To evaluate the role and therapeutic value of homocysteine (hcy)-inducible endoplasmic reticulum stress (ERS) protein with ubiquitin like domain 1 (Herpud1) in hcy-induced calcific aortic valve disease (CAVD). Background: The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited.Methods: In vivo , we use the low-density lipoprotein receptor (LDLR) and Herpud1 double knockout (LDLR-/-/Herpud1-/-) mice assessment of aortic valve calcification lesions, ERS activation, autophagy, and osteogenic differentiation of aortic valve interstitial cells (AVICs). We used siRNA to knock down Herpud1 in cultured Primary AVICs were isolated from mice to further validate our findings. Results: Herpud1 was highly expressed in calcified human and mouse aortic valves as well as primary aortic valve interstitial cells (AVICs). Herpud1 deficiency inhibited hcy-induced CAVD in vitro and in vivo. Herpud1 silencing activated cell autophagy, which subsequently inhibited hcy-induced osteogenic differentiation of AVICs. Hcy increased Herpud1 expression through the ERS pathway and promoted CAVD progression. ERS inhibitor 4-phenyl butyric acid (4-PBA) significantly attenuated aortic valve calcification in high methionine diet–fed low-density lipoprotein receptor-/- (LDLR-/-) mice by suppressing ERS and subsequent Herpud1 biosynthesis. Conclusions: These findings identify a previously unknown mechanism of Herpud1 upregulation in CAVD progression, suggesting that Herpud1 silencing or inhibition is a viable therapeutic strategy for arresting CAVD progression.

With the shortage of resources and the increasingly serious environmental pollution in China, green innovation has become a sustainable competition for a region. The Yangtze River Economic Belt (YREB) strategy is one of the most important strategies for the sustainable development of China’s economy under the new normal. Green innovation plays a linking role in the resources exchange and trade flow in YREB, and it is also the foundation and guarantee to implement the YREB strategy. The global environmental pollution and the weak recovery of world economy make the traditional extensive economic growth model unsustainable. Sustainable economic growth should focus on the quality of development and its external costs to the environment. In order to implement the concept of sustainable development, the improvement of logistics ecological efficiency is related to the quality of ecological civilization construction. Therefore, it is of theoretical and practical significance to study the measurement, evolution, and driving factors of coordinated development level of regional green innovation system. This paper proposes a super-slack-based measure (super-SBM) data envelopment analysis (DEA) model to measure the green innovation efficiency of 11 provinces and cities in YREB from 2008 to 2017, mastering its spatial and evolutionary characteristics, and conduct empirical analysis on the influencing factors. The empirical results indicate that economic development, government support, and industrial structure upgrading are the leading forces to directly enhance the green technology innovation ability of cities in the Yangtze River Economic belt and play the core driving role of green innovation. To further enhance the capacity of urban green innovation in the Yangtze River Economic belt, we will increase the government’s support for green innovation, optimize the environmental governance model, promote the green upgrading of industrial structure, and enhance the enthusiasm of enterprises for green innovation.

Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

Doxorubicin (DOX) is a highly effective and extensively used chemotherapeutic drug but is limited by its cardiotoxicity. In our previous study, we showed that DOX-induced cardiotoxicity (DIC) triggers autophagy and pyroptosis. Sirtuin 3(SIRT3) is an NAD + -dependent deacetylase of the mitochondria that regulates autophagy. However, it is unknown if the protective effects of SIRT3 on DOX-induced cardiotoxicity involve the inhibition of NLRP3 inflammasome activation. In this study, we constructed in vivo and in vitro DIC models to investigate the effects and potential mechanisms of SIRT3 on DIC. We found that the overexpression of SIRT3 remarkably attenuated DIC through inhibition of the NLRP3 inflammasome. Moreover, we found that the overexpression of SIRT3 restored the dynamic balance of autophagosome/autolysosomes by targeting the mTOR/ULK1 signaling pathway. Application of the mTOR agonist MHY1485 further demonstrated that SIRT3 inhibited NLRP3 inflammasome activation by regulating autophagy. Collectively, the results suggest that SIRT3 effectively attenuates the cardiotoxicity of DOX and provides a theoretical foundation for further exploration of DIC.

Background: Dietary polyphenols help to prevent cardiovascular diseases, and interactions between polyphenols and gut microbiota are known to exist. In this study, we speculated that gut microbiota-mediated metabolite regulation might contribute to the anticardiotoxic effects of yellow wine polyphenolic compound (YWPC) in doxorubicin (DOX)-treated rats. Methods: 16S-rDNA sequencing was performed to analyze the effects of YWPC on the gut microbiota in DOX-treated rats (n=6). Antibiotics were used to investigate the contribution of the altered microbiome to the role of YWPC (n=6). Plasma metabolomics were also analyzed by untargeted gas chromatography-mass spectrometry systems. Results: YWPC ameliorated DOX-mediated cardiotoxicity, as evidenced by increased cardiac and mitochondrial function and reduced levels of inflammation and myocardial apoptosis ( P Escherichia – Shigella , Dubosiella , and Allobaculum , along with enrichment of Muribaculaceae_unclassified , Ralstonia , and Rikenellaceae_RC9_gut_group in the gut, suggested that YWPC ameliorated DOX-induced microbial dysbiosis. YWPC also influenced the levels of metabolites altered by DOX, resulting in lower arachidonic acid and linoleic acid metabolism and higher tryptophan metabolite levels ( P Conclusions: YWPC protected against DOX-induced cardiotoxicity in a gut microbiota–dependent manner. This supports the use of dietary polyphenols as a therapeutic approach for the treatment of cardiovascular diseases via microbiota regulation.

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway.

Introduction Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug, but the clinical application of DOX is seriously limited by its dose-dependent cardiotoxicity. Ononin is a natural isoflavone glycoside and plays a key role in modulating apoptosis related signaling pathways. The aim of this study was to assess the possible cardioprotective effects of Ononin in DOX-induced cardiotoxicity and the underlying molecular mechanisms. Materials and methods Wistar rats were treated with normal saline, DOX with or without Ononin. After the last administration, cardiac function was evaluated by echocardiography. Rats were then sacrificed for histological and TUNEL analyses, with immunological detection for β-actinin, Bax, Bcl-2, GRP78, CHOP and SIRT3. An enzyme-linked immunosorbent assay was performed to assess the myocardial injury markers. H9C2 cells were treated with vehicle, DOX with or without Ononin. Then, 3-TYP was used to find out the relationship between ER stress and SIRT3. Results Ononin treatment ameliorated DOX-induced myocardial injury as demonstrated by echocardiography. Ononin partially restored DOX-induced cardiac dysfunction, both LVEF and LVFS were increased under the cotreatment of Ononin. Ononin also inhibited DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. DOX group had a higher Bax/Bcl-2 ratio, GRP78 and CHOP expression then control group, but Ononin treatment improved these results. This effect was associated with SIRT3 activity, moreover, selective inhibition of SIRT3 blocked the protective effects of Ononin. Conclusion In the present study, we tested the hypothesis that Ononin may protect against DOX-induced cardiomyopathy through ER stress both in vitro and in vivo. Ononin is able to protect against DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, this effect may via stimulation of the SIRT3 pathway.

Aims Doxorubicin (DOX), a widely used powerful chemotherapeutic component for cancer treatment, can give rise to severe cardiotoxicity that limits its clinical use. Pyroptosis is characterized by proinflammation and has been defined as a new type of programmed cell death in recent years. However, whether the DOX-induced cardiotoxicity is related to pyroptosis, and if so, which genes are involved in this process is largely unknown. In this study, we sought to identify the effect of DOX on cardiomyocyte pyroptosis and further reveal the underlying regulatory mechanism. Methods and results In vitro and in vivo experiments showed that DOX treatment induced cardiomyocyte pyroptosis as evidenced by increased cell death and upregulated expression levels of NLR family pyrin domain containing 3 (NLRP3), caspase-3, IL-1β, IL-18 and GMDSD-N. Inhibition of NLRP3 rescued the DOX-induced pyroptosis. qRT-PCR showed that TINCR lncRNA was upregulated by DOX treatment and knockdown of TINCR reversed the DOX-induced pyroptosis both in vitro and in vivo. Mechanistic investigations revealed that TINCR increased NLRP3 level via recruiting IGF2BP1 to enhance NLRP3 mRNA. And the effect of TINCR on cardiomyocyte pyroptosis was attenuated by the inhibition of NLRP3 or IGF2BP1. Finally, TINCR was not involved in DOX-induced pyroptosis in cancer cells. Conclusion TINCR mediates the DOX-induced cardiotoxicity and pyroptosis in an IGF2BP1-dependent manner. Therefore, TINCR may serve as a promising therapeutic target to overcome the cardiotoxicity of chemotherapy for cancer therapy.

Hyperhomocysteinemia (HHcy) is a highly-related risk factor in vascular smooth muscle cell (VSMC) phenotypic modulation and atherosclerosis. Growing evidence indicated that autophagy is involved in pathological arterial changes. However, the risk mechanisms by which homocysteine and VSMC autophagy interact with cardiovascular disease are poorly understood. This study verified the homocysteine-responsive endoplasmic reticulum protein promotion of VSMC phenotypic switching, and the formation of atherosclerotic plaque in vitro. We found that impaired autophagy, as evidenced by decreased levels of MAP1LC3B II/MAP1LC3B I, has a vital role in HHcy-induced human aortic (HA)-VSMC phenotypic switching, with a decrease in contractile proteins (SM α-actin and calponin) and an increase in osteopontin. Knockdown of the essential autophagy gene Atg7 by small interfering RNA promoted HA-VSMC phenotypic switching, indicating that impaired autophagy induces phenotypic switching in these cells. HHcy co-treatment with rapamycin triggered autophagy, which alleviated HA-VSMC phenotypic switching. Finally, we found that Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor for maintaining genomic stability by resisting oxidative stress and restoring autophagy, is closely involved in this process. HHcy clearly decreased KLF4 expression. KLF4-specific siRNA aggravated defective autophagy and phenotypic switching. Mechanistically, KLF4 regulated the HHcy-induced decrease in HA-VSMC autophagy via the m-TOR signaling pathway. In conclusion, these results demonstrated that the KLF4-dependent rapamycin signaling pathway is a novel mechanism underlying HA-VSMC phenotypic switching and is crucial for HHcy-induced HA-VSMCs with defective autophagy to accelerate early atherosclerosis.

The role of endoplasmic reticulum (ER) stress in cardiovascular disease is now recognized. Tauroursodeoxycholic acid (TUDCA) is known to have cardiovascular protective effects by decreasing ER stress. This study aimed to assess the ability of TUDCA to decrease ER stress, inhibit dedifferentiation of vascular smooth muscle cells (VSMCs), and reduce in-stent restenosis. The effect of TUDCA on dedifferentiation of VSMCs and ER stress was investigated in vitro using wound-healing assays, MTT assays, and western blotting. For in vivo studies, 18 rabbits were fed an atherogenic diet to induce atheroma formation. Bare metal stents (BMS), BMS+TUDCA or Firebird stents were implanted in the left common carotid artery. Rabbits were euthanized after 28 days and processed for scanning electron microscope (SEM), histological examination (HE), and immunohistochemistry. In vitro TUDCA (10–1000 μmol/L) treatment significantly inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration in VSMCs in a concentration-dependent manner and decreased ER stress markers (IRE1, XBP1, KLF4, and GRP78). In vivo, we confirmed no significant difference in neointimal coverage on three stents surfaces; neointimal was significantly lower with BMS+TUDCA (1.6 ± 0.2 mm2) compared with Firebird (1.90 ± 0.1 mm2) and BMS (2.3 ± 0.1 mm2). Percent stenosis was lowest for BMS+TUDCA, then Firebird, and was significantly higher with BMS (28 ± 4%, 35 ± 7%, 40 ± 1%; respectively; P

Background: Recent studies have revealed that a novel selective sodium-glucose cotransporter 1 (SGLT1) inhibiton has shown beneficial effects in cardiovascular diseases. However, the question of whether SGLT1 inhibition influences diabetic cardiomyopathy (DCM) remains unanswered. In this study, we investigated the influence and underlying mechanism of SGLTI inhibition on DCM.Methods: SGLT1 levels were measured in diabetic patients with similar conditions who visited our hospital from January to December 2019. Wistar male rats (n = 50) were divided into five groups: control, diabetes induced by streptozotocin infusion, and diabetes treated with 0.5, 1.0, or 1.5 mg/kg mizagliflozin via stomach gavage for 12 weeks. H9C2 cardiomyocytes were treated with mizagliflozin and then exposed to a high glucose concentration (30 mmol/L). TUNEL assays were performed, and bcl2, bax, p-p38, p-Erk, p-JNK and caspase-3 levels were measured. We used siRNA and an SGLT1 overexpression plasmid to detect the effects of SGLT1.Results: SGLT1 levels were significantly elevated in DCM patients, and receiver operating characteristic (ROC) curve analysis identified SGLT1 as influencing DCM. The area under the curve (AUC) was 0.705 (p < 0.05), with 65.8% sensitivity, and 62.2% specificity. SGLT1 inhibition appeared to attenuate apoptosis in DCM via the JNK and p38 pathway.Conclusion: SGLT1 can be used as a marker for the diagnosis of DCM, and SGLT1 inhibition can attenuate apoptosis, thereby suppressing DCM development via the JNK and p38 pathway.

Doxorubicin (DOX) is well-known for its potent antitumor activity but limited by its multiple and serious adverse effects. A major adverse effect is acute cardiotoxicity; yet, its mechanism has not been elucidated. Fucoidan is a multifunctional and nontoxic polysaccharide that is widely studied because of its favorable biological activities and safety. Hence, we proposed that fucoidan may play a protective role in DOX-induced acute cardiotoxicity without causing additional side effects. Sprague-Dawley rats were injected intraperitoneally with a single high dose of DOX to induce acute cardiac injury. Fucoidan was administered orally before DOX injection and AG490, a JAK2 inhibitor, was applied to verify the participation of the JAK2/STAT3 pathway. In vitro, H9C2 cells were treated with the same drugs at different concentrations and intervention times. in vivo and in vitro results demonstrated that DOX administration induced myocardial damage accompanied by acceleratory apoptosis and deficient autophagy in heart tissues or cells, which could be significantly improved by fucoidan supplement. AG490 partly abolished the cardioprotective effects of fucoidan, suggesting the involvement of JAK2 signaling. Additionally, western blotting revealed DOX-induced JAK2/STAT3 pathway activation, which was enhanced by fucoidan and weaken by AG490. Hence, fucoidan exerted a favorable effect on DOX-induced cardiotoxicity by enhancing autophagy and suppressing apoptosis in a JAK2/STAT3-dependent manner, which may provide a promising and novel therapeutic strategy against negative chemotherapy-induced effects.

An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help.The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis.Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.22), P0.00001; current smoking: OR =2.51, 95% CI(1.39, 3.32), P = 0.0006). The proportion of underlying diseases such as hypertension, diabetes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (diabetes: OR=3.68, 95% CI (2.68, 5.03), P0.00001; hypertension: OR = 2.72, 95% CI (1.60,4.64), P = 0.0002; cardiovascular disease: OR = 5.19, 95% CI(3.25, 8.29), P0.00001; respiratory disease: OR = 5.15, 95% CI(2.51, 10.57), P0.00001). Clinical manifestations such as fever, shortness of breath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.82), P = 0.003;shortness of breath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P0.00001]. Laboratory examination such as aspartate amino transferase(AST)40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI)28pg/mL, procalcitonin(PCT)0.5ng/mL, lactatede hydrogenase(LDH)245U/L, and D-dimer0.5mg/L predicted the deterioration of disease while white blood cells(WBC)4 × 10Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.

The pro-aging miRNA, miR-34a, is hyperactivated in the cardiac myocardial tissues of patients and mice with diabetes, leading to diabetic cardiomyopathy (DCM). Increasing evidence suggests that dihydromyricetin (DHM) can be used to effectively treat cardiomyopathy. In this study, we investigated whether DHM affects the expression of miR-34a in DCM. The expression of miR-34a in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice was determined by microRNA isolation and quantitative reverse transcription-polymerase chain reaction. Lipofectamine 3000 was used to transfect cardiomyocytes with miR-34a inhibitor, miR-34a mimics, and miR-control. These agents were intravenously injected into the tail vein of streptozotocin-induced diabetic mice. Autophagy and apoptosis were assessed in high-glucose-induced cardiomyocytes and cardiac tissue in diabetic mice by western blotting, immunofluorescence, Masson staining, hematoxylin and eosin staining (H&E), and electron microscopy. DHM clearly ameliorated the cardiac dysfunction in the diabetic mice. The expression of miR-34a was up-regulated in high-glucose-induced cardiomyocytes and in the hearts of diabetic mice, thus impairing autophagy. Treatment with DHM decreased the expression of miR-34a and rescued the impairment of autophagy in high-glucose-induced cardiomyocytes and in the heart tissue of diabetic mice, while the miR-34a mimic offset the effect of DHM with respect to the development of DCM by inhibiting autophagy. By decreasing the expression of miR-34a, DHM restores impaired autophagy, and thus ameliorates DCM. Therefore, DHM may potentially be used in the treatment of DCM.

To examine the clinical efficacy of Jiawei Shenfu decoction on tumor necrosis factor-al- pha (TNF-α) and nuclear factor-kappa B (NF-κB) levels in patients who have chronic heart failure with syndromes of deficiency of heart Yang.A total of 63 patients with syndromes of deficiency of heart Yang (chronic heart failure) were enrolled. Patients were randomly divided into the control group and Jiawei Shenfu group. All patients received standard medications for treatment of chronic heart failure. Patients in the Jiawei Shenfu group were additionally provided Jiawei Shenfu decoction one dose daily. Treatments continued for 4 consecutive weeks. The primary endpoint was the change in plasma B-type natriuretic peptide (BNP), NF-κB, and TNF-α levels during 4 weeks of treatment.At the 4-week follow-up, a significant reduction in BNP levels compared with baseline was observed in both groups, but the Jiawei Shenfu decoction group showed a significantly greater reduction than did the control group. The Jiawei Shenfu group also showed superior performance regarding the Minnesota Living with Heart Failure Questionnaire score, the Chinese medicine syndrome score, heart rate, left ventricular ejection fraction, and 6-min walking distance compared with the control group. The degree of changes in NF-κB and TNF-α levels in the Jiawei Shenfu group was more significant than that in the control group.Routine medicine combined with Jiawei Shenfu decoction for patients with heart Yang deficiency syndrome in chronic heart failure can improve the left ventricular ejection fraction and cardiac function, and reduce BNP levels. The mechanism may be related to inhibition of pro-inflamma- tory cytokines and the NF-κB-induced kinase pathway, leading to amelioration of the inflammatory response.

Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug whose clinical application is limited by serious cardiotoxic side effects. Dihydromyricetin (DHM), a flavonoid compound extracted from the Japanese raisin tree (Hovenia dulcis), is cardioprotective in patients with heart failure; however, the underlying mechanisms are poorly understood. The aim of this study was to assess the possible anti-inflammatory properties of DHM in a rat model of DOX-induced cardiotoxicity and DOX-treated H9C2 cells, and gain insights into the molecular mechanisms that mediate these effects. The results showed that DHM treatment significantly improved the myocardial structure and function in DOX-exposed rats by alleviating NLRP3 inflammasome-mediated inflammation. DHM also inhibited DOX-induced activation of the NLRP3 inflammasome in H9C2 cells. This effect was mediated by inhibition of caspase-1 activity, suppression of IL-1β and IL-18 release, and upregulation of SIRT1 protein levels in vivo and in vitro. Moreover, selective inhibition of SIRT1 blocked the protective effects of DHM. Collectively, our findings indicate that DHM protects against DOX-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation via stimulation of the SIRT1 pathway.

Background Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. Methods To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp −/− and LDLR −/− double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo . We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro . Results HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR −/− mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp −/− /LDLR −/− mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR −/− mice. However, Herp deficiency had no effect on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation and collagen accumulation were observed in Herp −/− /LDLR −/− mice when compared with LDLR −/− mice. In vitro experiments demonstrated that Hcy caused VSMC phenotypic switching, promoted cell proliferation and migration; this was reversed by Herp depletion. We achieved similar results via inhibition of ER stress using 4-phenylbutyric-acid (4-PBA) in Hcy-treated VSMCs. Conclusion Herp deficiency inhibits the phenotypic switch of VSMCs and the development of atherosclerosis, thus providing novel insights into the role of Herp in atherogenesis.

Many studies support the cardioprotective effects of folic acid (FA). We aimed to evaluate the utility of FA supplementation in preventing the development of atherosclerotic in low‐density lipoprotein receptor‐deficient (LDLR−/−) mice and to elucidate the molecular processes underlying this effect. LDLR−/− mice were randomly distributed into four groups: control group, HF group, HF + FA group and the HF + RAPA group. vascular smooth muscle cells (VSMCs) were divided into the following four groups: control group, PDGF group, PDGF + FA group and PDGF + FA + RAPA group. Blood lipid levels, oxidative stress and inflammatory cytokines were measured. Atherosclerosis severity was evaluated with oil red O staining. Haematoxylin and eosin (H&E) staining was used to assess atherosclerosis progression. Immunohistochemical staining was performed with antismooth muscle α‐actin (α‐SMA) antibodies and anti‐osteopontin (OPN) antibodies that demonstrate VSMC dedifferentiation. The protein expression of α‐SMA, OPN and mechanistic target of rapamycin (mTOR)/p70S6K signalling was detected by Western blot analysis. FA and rapamycin reduced serum levels of total cholesterol, triacylglycerol, LDL, inhibiting oxidative stress and the inflammatory response. Oil red O and H&E staining demonstrated that FA and rapamycin inhibited atherosclerosis. FA and rapamycin treatment inhibited VSMC dedifferentiation in vitro and in vivo, and FA and rapamycin attenuated the mTOR/p70S6K signalling pathway. Our findings suggest that FA attenuates atherosclerosis development and inhibits VSMC dedifferentiation in high‐fat‐fed LDLR−/− mice by reduced lipid levels and inhibiting oxidative stress and the inflammatory response through mTOR/p70S6K signalling pathway.

BACKGROUND Developing a simple and efficient method of obtaining primary cultured VSMCs is necessary for basic cardiovascular research. MATERIAL AND METHODS The procedure of our new method mainly includes 6 steps: isolation of the aortic artery, removal of the fat tissue around the artery, separation of the media, cutting the media into small tissue blocks, transferring the tissue blocks to cell culture plates, and incubation until the cells reach confluence. The cells were identified as VSMCs by morphology and immunofluorescence. Then, VSMCs obtained by this new tissue explants method, the traditional tissue explants method, the enzyme digestion method, and A7r5 cell line were divided into 4 groups. The purity of cells was test by multiple fluorescent staining. Western blotting was used to investigate the phenotype of VSMCs obtained by different methods. RESULTS Cells began to grow out at about 8 days and became relatively confluent within 16 days. Compared with VSMCs from the traditional tissue explants method and enzyme digestion method or A7r5 cell line, VSMCs obtained by our method showed higher purity and manifested a more "contractile" phenotype characteristic. CONCLUSIONS We have conquered the disadvantages in the previous primary culture methods and established a simple and reliable way to isolate and culture rat aortic VSMCs with high purity and stability.

Background Angiotensin II (Ang II)-induced damage to endothelial cells (ECs) plays a crucial role in the pathogenesis of atherosclerosis. This study aimed to investigate the role of microRNA-384 (miR-384) in endothelial cell apoptosis. Methods The expression of five various miRNAs in Ang II-treated human umbilical vein endothelial cells (HUVECs) were detected by qPCR. The Ang II-induced apoptosis of HUVECs was determined by flow cytometry, TUNEL staining and western blot. Endoplasmic reticulum (ER) stress markers were detected by western blot analysis. The target gene of miR-384 was determined by bioinformatics analyses. qPCR, western blotting and immunofluorescence were performed to determine the expression level of homocysteine inducible ER protein with ubiquitin like domain 1 (Herpud1). Results miR-384 expression level was significantly decreased in Ang II-treated HUVECs. Ang II-induced HUVEC apoptosis was accompanied by the occurrence of ER stress. A decreased rate of HUVEC apoptosis and a decreased rate of ER stress were observed following restoration of miR-384 expression. Herpud1 expression level was increased in HUVECs treated with Ang II, and miR-384 mimics effectively inhibited Herpud1 expression. Mechanistically, miR-384 directly targets the 3′-untranslated region of Herpud1. Furthermore, effects of miR-384 on HUVECs apoptosis and ER stress were at least partly reversed by knockdown of Herpud1 expression. Conclusion The results of the present study collectively indicated that miR-384 expression level was downregulated in Ang II-treated HUVECs and miR-384 overexpression protected HUVECs against Ang II-induced apoptosis by negatively regulating Herpud1. These findings point towards new strategies by which apoptosis of ECs can be suppressed.

Introduction A left common pulmonary vein (LCPV) is a common anatomical variant in atrial fibrillation (AF) patients. Whether an LCPV influences outcomes of repeated radiofrequency catheter ablation (RFCA) for AF has not been elucidated. Methods From a prospectively collected database, we enrolled 154 patients who received repeated RFCA for recurrent AF after the initial RFCA (56 ± 9 years, 72% paroxysmal AF, 32 patients with an LCPV, and 122 patients with typical left-sided pulmonary veins [PVs]). Median postprocedural follow-up was 26 months. The primary outcome was an episode of AF, atrial tachyarrhythmia, or atrial flutter lasting for more than 30 seconds, after the 3 months blanking period following the repeated procedure. Results After the follow-up period, 75 patients suffered recurrence after repeated ablation. In the Kaplan-Meier analysis, an LCPV was significantly associated with less recurrence (hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.28-0.79; P = 0.005). In subgroup analysis, the significant association persisted in paroxysmal AF patients. Regarding persistent AF patients, an LCPV tended to be associated with less recurrence with no statistical significance (HR: 0.40; 95% CI: 0.20-1.03; P = 0.067). In multivariate analyses, an LCPV still independently predicted freedom from recurrence (HR: 0.44; 95% CI: 0.22-0.88; P = 0.02). Conclusion Compared with typical left-sided PVs, an LCPV was independently associated with better outcomes after repeated RFCA of AF, particularly in patients with paroxysmal AF.

Background: The incidence of recurrent arrhythmia after catheter ablation (CA) for atrial fibrillation (AF) is unacceptable. Short-term antiarrhythmic drug (AAD) treatment following CA was presumed to be effective in reducing recurrent arrhythmia. Objective: To fully evaluate the efficacy of short-term use of AADs following CA for AF in preventing recurrence of atrial tachyarrhythmias. Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched up until May 1, 2016. We enrolled randomized controlled trials (RCTs) that evaluated the efficacy of short-term use of AADs following CA for AF in preventing early and/or late recurrence of atrial tachyarrhythmias. The statistical analyses were performed using Review Manager Version 5.3. Results: Six RCTs were included in this analysis, involving a total of 2764 patients. The frequency of early recurrence of atrial tachyarrhythmias was 39.5% in the AAD group (556 of 1407) and 47.2% (640 of 1357) in the control group. The pooled risk ratio of the AAD group to the control group was 0.78 (95% CI = 0.62-0.98). Regarding late recurrence of AF (LRAF), the incidence in the AAD group and the control group was 32.5% (420 of 1293) and 34.6% (450 of 1300), respectively. No significant difference was identified between the 2 groups (relative risk = 0.94, 95% CI = 0.85-1.05). Conclusions: Short-term use of AADs following CA for AF reduced the incidence of early recurrent atrial tachyarrhythmias but did not prevent LRAF.

The beneficial effect of Chinese rice wine on atherosclerosis has been proved, but the exact components that have the cardiovascular protective effect are still unknown. This study aimed to explore the exact ingredients in Chinese rice wine that could inhibit homocysteine (Hcy)-induced vascular smooth muscle cell (VSMC) proliferation and migration. VSMCs were divided into 7 groups: control, Hcy (1 mmol/L), Hcy + oligosaccharide, Hcy + polypeptides, Hcy + polyphenols, Hcy + alcohol, and Hcy + Chinese rice wine. methyl thiazolyl tetrazolium (MTT) assay, Transwell chambers, and wound-healing assay were used to test the proliferation and migratory ability of the VSMCs. Western blot and gelatin zymography were used to investigate the expressions and activities of metal matrix proteinase 2/9 (MMP-2/9) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in VSMCs. Polypeptides and polyphenols in the Chinese rice wine reduced the proliferation and migration ability of the VSMCs. Furthermore, they also decreased the expression and activity of MMP-2/9 but had no obvious impact on the expression of TIMP-2 in each group. This study further confirms that polypeptides and polyphenols in the Chinese rice wine could inhibit Hcy-induced proliferation and migration of VSMCs and maintain the balance between matrix metalloproteinases (MMPs) and TIMPs.

Objective The objective of this study was to determine similarities in the effect of yellow wine as compared to statin and the possibility that yellow wine inhibits tumour necrosis factor- α(TNF-α)-induced nitric oxide (NO) synthesis, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) in cultured rat vascular endothelial cells (VECs).Methods We isolated VECs, and cultivated and purified Sprague Dawley (SD) rat thoracic aortas in vitro. We selected the optimal wine concentration using clonogenic and MTT assays to measure cell survival. Next, we divided the cells into 9 groups: (1) control, (2) TNF-α, (3) TNF- α+ rosuvastatin (10 μmol/L), (4) TNF- α+ ethanol 0.5%, (5) TNF- α+ yellow wine 0.5%, (6) TNF- α+ ethanol 1.0%, (7) TNF- α+ yellow wine 1.0%, (8) TNF- α+ ethanol 1.5%, and (9) TNF- α+ yellow wine 1.5% and they were given the corresponding treatment for 24 h. We determined NO production with nitrate reductase. We then measured...

The rapid growth of China’s economy and the progress of industrialization have gradually led to serious resource depletion and environmental degradation. The Yangtze river economic belt (YREB) strategy is one of the most important strategies for the sustainable development of the “new normal” economy in China. Logistics industry, as a foundation that guarantees to implement the YREB strategy, plays a linking role in the resources exchange and trade flow in the YREB. Therefore, maximizing economic benefits while using the least amount of resources and the least damage to the environment is an urgent and critical issue for achieving sustainable development. This paper proposes to combine a super slack-based measure (super-SBM) data envelopment analysis (DEA) model and the global Malmquist index to evaluate the logistics ecological efficiency of 11 provinces/cities in the YREB from 2004 to 2016. Later, global and local Moran’s indexes are used to analyze the spatial autocorrelation of logistics ecological efficiency. Finally, a spatial econometric model is proposed to study how the influencing factors interference affect logistics ecological efficiency. The empirical results show that: (1) Compared to economically underdeveloped areas, the upstream areas of the YREB exhibit higher logistics ecological efficiency; (2) On the whole, the positive effects of technical changes are stronger, the growth of logistics ecological efficiency is driven mainly by technological progress; (3) Significant spatial correlation exist among the logistics ecological efficiency of the YREB, the upstream regions is more efficient and tend to have a positive spillover effect on neighboring provinces; (4) Foreign direct investment, government intervention, level of economic development and human capital have positive effects on the logistics ecological efficiency, whereas industrial structure, environmental regulation and logistics energy intensity have negative impacts.

With the development of oil recovery technology, ultrasonic technology has been involved in oil production and oilfield development. The mechanism of ultrasonic wave plugging in near well is different from the conventional oil recovery technology. Ultrasonic oil production technique is an effective method to enhance oil production with low cost, good applicability, and no environmental pollution. The core part of ultrasonic oil production equipment for Enhanced Oil Recovery is a high-power ultrasonic transducer. The continuous high-power ultrasound is used to treat the reservoir, which changes the pore structure, the physical property and the state of the fluid, thus improving the permeability and flows conditions of the reservoir, and increasing the oil yield and oil recovery. Ultrasonic oil recovery equipment includes the generation of high-power ultrasonic signals, long-distance transmission and the conversion of electrical energy to acoustic energy. In this paper, state-of-the-art on the development of ultrasonic oil production devices for Enhanced Oil Recovery in China is introduced. The purpose of this paper is to provide a reference for the development of high-power ultrasonic oil extraction equipment and its promotion in tertiary oil recovery technology.

Atherosclerosis is a common cardiovascular disorder and is characterized by damage of endothelial cells, cell inflammation, hyper-proliferation of vascular smooth muscle cells and the accumulation of extracellular lipids and fibrous tissues. In this study, we firstly examined the expression level of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) in homocysteine (Hcy)-stimulated human aortic smooth muscle cells (HASMCs), and then looked into the potential molecular signaling axis of linc-ROR in regulating the proliferation and migration of HASMCs. Hcy promoted HASMC proliferation and up-regulated linc-ROR expression. Functional studies showed that linc-ROR exerted enhanced actions on the proliferation and migration of HASMCs. In addition, linc-ROR acted as a competing endogenous RNA for miR-195-5p and repressed the miR-195-5p expression in HASMCs. Linc-ROR was up-regulated the miR-195-3p was down-regulated in the plasma from CAD patients when compared to normal controls. Furthermore, fibroblast growth factor 2 (FGF2) was identified as a target of miR-195-5p and was negatively regulated by miR-195-5p in HASMCs. The rescue experiments revealed that linc-ROR-mediated HASMC proliferation and migration may be via regulating miR-195-5p/FGF2 axis. Linc-ROR inhibition blocked the miR-195-5p/FGF2 signaling in Hcy-treated HASMCs, and this effect may also involve in the miR-195-5p/FGF2 axis. To summarize, the data of the present study identified the up-regulation of linc-ROR in Hcy-stimulated HASMCs, and further mechanistic functional studies revealed that linc-ROR promoted HASMC proliferation and migration via regulating miR-195-5p/FGF2 axis. The present study provided the novel actions of linc-ROR in regulating HASMC proliferation and migration, which may be related to the pathophysiology of atherosclerosis.

Angiotensin II (Ang II) is reported to be involved in the development of various cardiovascular diseases by disrupting microvessel permeability, however, the underlying mechanism remains to be elucidated. The present study aimed to investigate the mechanism by which Ang II disrupts microvascular permeability. Rat endothelial cells were subjected to primary culture and identification. Cells in passages 4‑7 were then used for the following experiments. The cells were divided into control, Ang II, and Ang II + valsartan groups, and reverse transcription‑quantitative polymerase chain reaction and western blot analyses were perform to evaluate the expression of zonula occludens‑1 (ZO‑1) and vascular endothelial (VE)‑cadherin in the cells. The distribution of ZO‑1 protein was also detected using immunofluorescence assays. It was found that, compared with the control group, lower expression levels of ZO‑1 and VE‑cadherin were present in the Ang II group (P

Background If transformation from persistent atrial fibrillation (AF) to paroxysmal AF after catheter ablation had impacts on the outcome of repeated ablation was unclear. This study aimed to explore whether the type of recurrent AF after ablation for persistent AF was associated with recurrence after repeated ablation. Methods and results This was a retrospective cohort study. 116 persistent AF patients undergoing the second ablation due to a failed initial ablation were enrolled in our study. Patients with recurrent paroxysmal AF after initial ablation were categorized as Group A (47 patients) while those with recurrent persistent AF were categorized as Group B (69 patients). The study endpoint was defined as any episode of AF, atrial tachyarrhythmia or atrial flutter lasting for >30 s, after the 3 month blanking period following repeated procedure. After 3–72 months (median: 24 months) of follow-up from repeated ablation, 54 (47%) patients suffered from recurrence after repeated ablation. In univariate analyses, Group B suffered a higher risk for recurrence than those in Group A (hazard ratio: 2.05, 95% confidence interval: 1.14–3.70, P = 0.01). Besides recurrent AF type, larger left atrial dimension at repeated procedure and pulmonary vein reconnection also predicted success of repeated ablation. In multivariate analysis, patients in Group B still had a 1.91-fold higher risk for recurrence than those in Group A (HR: 1.91, 95% CI: 1.06–3.44, P = 0.03). Conclusions After persistent AF ablation, transformation from persistent AF to paroxysmal AF is independently associated with success of repeat ablation.

SummaryWhat is known and objective Uninterrupted warfarin during cryoballoon ablation (CB-A) of atrial fibrillation (AF) has been widely accepted. However, to our knowledge, no previous studies exist investigating the optimal intensity of anticoagulation with warfarin for CB-A. This study aimed to evaluate the efficacy and safety of uninterrupted low-intensity warfarin for CB-A of AF in the elderly. Methods Paroxysmal AF patients (age ≥ 70 years) who underwent CB-A were enrolled prospectively. The participants were stratified into 2 groups based on international normalized ratio (INR) before ablation (INR in group A: 1.5 to 2.0; INR in group B: 2.0-2.5). Primary endpoints included periprocedural thromboembolic complications and major bleeding. Secondary endpoints were new asymptomatic cerebral emboli (ACE) and minor bleeding. Results and discussion A total of 144 patients were enrolled (group A: 65; group B: 79). In group A, the use of concomitant antiplatelet drugs was more common. Also, the mean HAS-BLED score was significantly higher (2.4 ± 0.8 vs 2.0 ± 0.6, P

Cardiac fibrosis is a major pathological manifestation of diabetic cardiomyopathy (DCM), which leads to cardiac remodeling, dilated cardiomyopathy and congestive heart failure. Human cardiac fibroblasts (HCF) constitute the predominant cell type in the heart and matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are also involved in cardiac fibrosis. However, it is unclear whether high glucose levels affect the expression of MMPs and TIMPs in HCF. Sodium‑glucose cotransporter (SGLT) inhibitors have been developed as therapeutic agents and the anti‑DCM effect of SGLT inhibitors has been demonstrated by previous studies. However, whether SLGT inhibitors protect the diabetic heart by directly inhibiting the SGLTs in HCF in addition to lowering the blood glucose levels, has not yet been determined. In the present study, increased MMP‑2 expression was noted in HCFs in response to high glucose levels, which may be reversed by phlorizin (inhibits both SGLT1 and SGLT2), but not dapagliflozin (inhibits SGLT2). In addition, SGLT1 was revealed to be present in the HCFs and high glucose level was demonstrated to increase SGLT1 expression, which may be attenuated by phlorizin. Therefore it was concluded that high glucose levels induced MMP‑2 expression in the HCFs, potentially by upregulating SGLT1. SGLT1 inhibition may be a novel strategy for the treatment of DCM.

Background: No previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly. Objective: Evaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly. Methods: This is a prospective randomized study. We enrolled AF patients (age ≥ 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding. Results: A total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B ( P = 0.10). Conclusions: Uninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly.

Background aims Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays an important role in the development of pulmonary arterial hypertension. However, the molecular regulatory mechanisms of TIMP-1 in the pulmonary arteries are not fully understood, especially in human pulmonary arterial smooth muscle cells (HPASMCs). We investigated the signaling pathway involved in the regulation of TIMP-1 in HPASMCs induced by transforming growth factor (TGF)-β1. Methods Cultured HPASMCs were incubated with different concentrations of TGF-β1 (0–40 ng/mL) for 24 h or with 10 ng/mL TGF-β1 for different times (1–48 h). Results Western blot, real-time polymerase chain reaction and enzyme-linked immunosorbent assay analyses showed that TGF-β1 enhanced the expression and secretion of TIMP-1 in a time-dependent and dose-dependent fashion. TGF-β1 could phosphorylate two of the three mitogen-activated protein kinases—extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, but not c-Jun NH2-terminal kinase. Of these kinases, only the inhibition of ERK1/2 by U0126, which was a specific inhibitor of mitogen-activated protein kinase/ERK1/2, effectively blocked the TGF-β1-induced expression of TIMP-1. Mithramycin, an inhibitor of Sp1 transcription factor, also significantly inhibited the expression of TIMP-1. Additionally, electrophoretic mobility shift assay showed that TGF-β1 could up-regulate the DNA-binding activity of Sp1 and that U0126 and mithramycin could effectively inhibit these events. Conclusions TGF-β1 could stimulate the expression and secretion of TIMP-1 in HPASMCs in a time-dependent and dose-dependent fashion, and ERK1/2 and Sp1 signaling pathways might be involved in these activities.

Objective: Folic acid (FA) supplementation reduces the risk of atherosclerosis and stroke. Phenotypic change from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays an important role in atherosclerosis development; however, the exact mechanisms remain unknown. This study aimed to assess whether FA through mammalian target of rapamycin (mTOR)/P70S6K signaling inhibits platelet derived growth factor (PDGF-BB) induced VSMC dedifferentiation. Methods: VSMCs from primary cultures were identified by morphological observation and α-smooth muscle actin (α-SM-actin, α-SMA) immunocytochemistry. Then, VSMCs were induced by PDGF-BB and treated with varying FA concentrations. Rapamycin and MHY-1485 were used to inhibit or activate the mTOR/P70S6K pathway, respectively. Next, MTT, Transwell, and wound healing assays were employed to assess proliferation and migration of VSMCs. In addition, Western blotting was used to evaluate protein levels of α-SMA, calponin, osteopontin, mTOR, p-mTOR, P70S6K and p-P70S6K in VSMCs. Results: VSMCs showed phenotypic alteration from differentiated to dedifferentiated cells in response to PDGF-BB. MTT, Transwell and wound healing assays showed that FA markedly inhibited proliferation and migration in PDGF-BB-induced VSMCs, in a time and concentration-dependent manner. FA treatment increased the expression levels of the contractile phenotype marker proteins α-SMA and calponin compared with VSMCs stimulated by PDGF-BB alone. Furthermore, FA significantly suppressed mTOR and P70S6K phosphorylation compared with PDGF-BB alone. Similar to FA, downregulation of mTOR signaling by rapamycin inhibited VSMC dedifferentiation. In contrast, upregulation of mTOR signaling by MHY-1485 reversed the FA-induced inhibition of VSMC dedifferentiation. Conclusion: Folic acid inhibits dedifferentiation of PDGF-BB-induced VSMCs by suppressing mTOR/P70S6K signaling.

Objective: To test the influence of homocysteine on the production and activation of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and on cell migration of cultured rat vascular smooth muscle cells (VSMCs). Also, to explore whether rosuvastatin can alter the abnormal secretion and activation of MMP-2 and TIMP-2 and migration of VSMCs induced by homocysteine. Methods: Rat VSMCs were incubated with different concentrations of homocysteine (50–5 000 μmol/L). Western blotting and gelatin zymography were used to investigate the expressions and activities of MMP-2 and TIMP-2 in VSMCs in culture medium when induced with homocysteine for 24, 48, and 72 h. Transwell chambers were employed to test the migratory ability of VSMCs when incubated with homocysteine for 48 h. Different concentrations of rosuvastatin (10−9–10−5 mol/L) were added when VSMCs were induced with 1 000 μmol/L homocysteine. The expressions and activities of MMP-2 and TIMP-2 were examined after incubating for 24, 48, and 72 h, and the migration of VSMCs was also examined after incubating for 48 h. Results: Homocysteine (50–1 000 μmol/L) increased the production and activation of MMP-2 and expression of TIMP-2 in a dose-dependent manner. However, when incubated with 5 000 μmol/L homocysteine, the expression of MMP-2 was up-regulated, but its activity was down-regulated. Increased homocysteine-induced production and activation of MMP-2 were reduced by rosuvastatin in a dose-dependent manner whereas secretion of TIMP-2 was not significantly altered by rosuvastatin. Homocysteine (50–5 000 μmol/L) stimulated the migration of VSMCs in a dose-dependent manner, but this effect was eliminated by rosuvastatin. Conclusions: Homocysteine (50–1 000 μmol/L) significantly increased the production and activation of MMP-2, the expression of TIMP-2, and the migration of VSMCs in a dose-dependent manner. Additional extracellular rosuvastatin can decrease the excessive expression and activation of MMP-2 and abnormal migration of VSMCs induced by homocysteine.

The objective of this study was to determine similarities in the effect of yellow wine as compared to statin and the possibility that yellow wine inhibits tumour necrosis factor-α (TNF-α)-induced nitric oxide (NO) synthesis, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1) in cultured rat vascular endothelial cells (VECs).We isolated VECs, and cultivated and purified Sprague Dawley (SD) rat thoracic aortas in vitro. We selected the optimal wine concentration using clonogenic and MTT assays to measure cell survival. Next, we divided the cells into 9 groups: (1) control, (2) TNF-α, (3) TNF-α + rosuvastatin (10 μmol/L), (4) TNF-α + ethanol 0.5%, (5) TNF-α + yellow wine 0.5%, (6) TNF-α + ethanol 1.0%, (7) TNF-α + yellow wine 1.0%, (8) TNF-α + ethanol 1.5%, and (9) TNF-α + yellow wine 1.5% and they were given the corresponding treatment for 24 h. We determined NO production with nitrate reductase. We then measured eNOS activity, and detected eNOS, iNOS, and ICAM-1 protein levels by Western blotting.Compared with the TNF-α group, NO production, eNOS activity, and eNOS protein expression in the rosuvastatin, and yellow wine 1.0%, and 1.5% groups were significantly increased. Protein expression of iNOS and ICAM-1 in the rosuvastatin, yellow wine 1.0%, and 1.5% groups were significantly decreased. Compared with the rosuvastatin group, eNOS, iNOS, and ICAM-1 protein expression in the yellow wine (0.5% -1.5%) groups were significantly different.Treatment with yellow wine increased NO production, eNOS activity, and eNOS protein expression, which decreases iNOS and ICAM-1 protein expression. We conclude that yellow wine may have similar beneficial effects as rosuvastatin on the cardiovascular system. These effects may be attributed to their anti-atherosclerotic actions.

To provide evidence that rosuvastatin may improve insulin-resistance and inhibit atherogenesis by modulating insulin signaling, and whether this effect occurs beyond its plasma cholesterol-lowering effect. Thirty-two 6-week-old low-density lipoprotein receptor deficient mice were randomized into 4 groups (n = 8 in each group): Normal control group (NC); High fat and high fructose diet group (HFF); HFF plus rosuvastatin group (HFFR); HFFR plus mevalonic acid group (HFFRMA). After 12 weeks, we measured fasting blood sugar, fasting insulin and cholesterol levels; the morphological concentrations of the aorta and aortic sinus; the expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the liver. Compared with other groups, fasting blood sugar and fasting insulin increased significantly in HFF group. Furthermore, HFF group had an increase in the morphological concentrations of the aorta and aortic sinus, but there was a significant decrease in the HFFRMA group and the HFFR group. Moreover, there was a high expression of insulin receptor substrate 2, phosphorylated insulin receptor substrate 2, protein kinase B, phosphorylated protein kinase B and the glucose transporter 4 in the HFFRMA and HFFR groups, but a low expression in the HFF group. No significant differences regarding each afore-mentioned index was observed in the HFFR and HFFRMA groups. Our data show that rosuvastatin may improve insulin-resistance and inhibit atherogenesis in HFF-fed mice by partially reversing the decrease in the insulin stimulated insulin receptor substrate 2/Phosphatidylinositol 3-kinase/protein kinase B/glucose transporter 4 pathway in the liver, and that this effect is independent of its cholesterol-lowering effect.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary vascular resistance and vascular remodeling leading to right heart failure and early death. The pathology of PAH is associated with endothelium dysfunction and vascular remodeling in pulmonary arteries. In diseased pulmonary arteries, the balance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) is broken down. In this process, TIMP are up-regulated, which inhibits MMP, promotes extracellular matrix (ECM) deposition and finally leads to vascular remodeling. So, what would happen to PAH if the expression of TIMP was down-regulated in diseased pulmonary vessels? We hypothesize that the attenuation of TIMP at the advanced stage of PAH might reverse severe PAH, via ameliorating vascular remodeling and endothelium repair.

Our previous study found that Chinese yellow wine could inhibit the production of homocysteine (HCY) induced extracellular matrix metalloproteinase-2 (MMP-2) in the cultured rat vascular smooth muscle cells. Little is known about the relationship between Chinese yellow wine and atherosclerosis or MMP-2 in vivo. Thirty-two LDL Receptor knockout mice on a high-fat and L-methionine diet developed plasma hyperhomocysteinemia and atherosclerosis. They were randomly divided into yellow wine group (n = 8), red wine group (n = 8), ethanol group (n = 8), and control group (n = 8), they were sacrificed after 14 weeks. There were no significant differences with plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in the four groups. Plasma HCY was significantly decreased in the yellow wine group compared to the other three groups (P < 0.01). Yellow wine and red wine groups significantly reduced the atherosclerosis lesion area compared to ethanol and control groups (P < 0.001). However, there was no significant discrepancy between the yellow wine group and red wine group. Compared to the control group and ethanol group, the production of MMP-2 reduced 26.8% and 23.6% in the aortic sinus and the activation of MMP-2 reduced 32.6% and 27.3% in the aortic arch in the yellow wine group; the production of MMP-2 reduced 25.7% and 22.4% in the aortic sinus and the activation of MMP-2 reduced 30.2% and 26.6% in the aortic arch in the red wine group. These results suggest that Chinese yellow wine and red wine can inhibit MMP-2 and improve atherosclerosis, and maybe both Chinese yellow wine and red wine have beneficial effects on cardiovascular disease by inhibiting MMP-2.