| cGMP Signaling and Modulation in Heart Failure Cyclic GMP (cGMP) represents a classic intracellular second messenger molecule. Over the past two decades, important discoveries have identified that cGMP signaling becomes deranged in heart failure, and that cGMP and its main kinase effector, Protein Kinase G, generally oppose the biological abnormalities contributing to heart failure, in experimental studies. These findings have influenced the design of clinical trials of cGMP-augmenting drugs in heart failure patients. At present, the trial results of cGMP-augmenting therapies in heart failure remain mixed. As detailed in this review, strong evidence now exists that Protein Kinase G opposes pathologic cardiac remodeling through regulation of diverse biological processes and myocardial substrates. Potential reasons for the failures of cGMP-augmenting drugs in HF may be related to biological mechanisms opposing cGMP, or due to certain features of clinical trials, all of which are discussed. Correspondence: Robert M. Blanton, MD. Molecular Cardiology Research Institute, Tufts Medical Center. 800 Washington Street, #080. Boston, MA, USA 02111. Telephone +1 617 636 7678 Fax +1 617 636 1444 Email: rblanton@tuftsmedicalcenter.org Sources of Support: NIH R01HL131831 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| Research progress of mechanisms and drug therapy for atherosclerosis on TLR pathway Recent reports have established atherosclerosis (AS) as a major factor in the pathogenetic process of cardiovascular diseases like ischemic stroke and coronary heart disease. Although the possible pathogenesis of AS remains to be elucidated, a large number of investigations strongly suggest that the inhibition of Toll-like receptors (TLRs) alleviates the severity of AS to some extent by suppressing vascular inflammation and the formation of atherosclerotic plaques. As pattern recognition receptors (PRRs), TLRs occupy a vital position in innate immunity, mediating various signaling pathways in infective and sterile inflammation. This review summarizes the available data on the research progress of AS and the latest antiatherosclerotic drugs associated with TLR pathway. Corresponding author. E-mail address: yunmanlicpu@hotmail.com (Y.-m. Li) E-mail address: huyahui324@163.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| FSTL3 induces lipid accumulation and inflammatory response in macrophages and associates with atherosclerosis FSTL3 as adipokine take part in dyslipidemia and inflammatory response, but the association of FSTL3 with atherosclerosis is unclear. This study indicated that FSTL3 showed significantly higher level (Control: 7.68±3.10 ng/mL versus AS: 9.29±2.37 ng/mL; P<0.001) in atherosclerosis, and FSTL3 expressed higher in plaque of ApoE knockout mice and located in macrophages. OxLDL induced expression and secretion of FSTL3, meanwhile, FSTL3 promoted lipid accumulation in macrophages. The advanced study found that FSTL3 upregulated CD36 and LOX-1 expression with dose-dependent manner, however, FSTL3 also evoked interleukin 1-β (IL1-β), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α (TNFα) and matrix metalloproteinase-9 (MMP-9) secretion in macrophages. On the contrary that downregulated FSTL3 attenuated expression of oxLDL induced CD36, LOX-1 and inflammatory cytokines expressing. All of these results demonstrated that FSTL3 as novelty cytokine take part in process of atherosclerosis through increasing lipid accumulation and inflammation via regulating CD36 and LOX-1 expression. Corresponding author: Ding Wenjun, MD, PhD Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital 180 Feng Lin road Shanghai 200025 People’s Republic of China Tel: +86 21 64041990 Fax: +86 21 64041990 Email address: doctor_dingwj@163.com Co-corresponding author: Wang Chunsheng, MD, PhD Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital 180 Feng Lin road Shanghai 200025 People’s Republic of China Tel: +86 21 64041990 Fax: +86 21 64041990 Email address: doctor_wangcs@163.com This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| Long non-coding RNA NEAT1 promotes myocardiocyte apoptosis and suppresses proliferation via regulation of miR-129-5p Recent studies have revealed the important role of long non-coding RNAs (lncRNAs) in heart development and pathogenesis. This study was aimed to investigate the role of NEAT1 in hypoxia-induced cardiac injury and explore its possible molecular mechanism. Real-time PCR (RT-PCR) was used to determine the relative RNA expression of NEAT1 and its potential target microRNA (miRNA), miR-129-5p, in the plasma of patients with acute myocardial infarction, heart failure, and angina, as well as in H2O2-treated H9c2 cells. The role of NEAT1 overexpression or inhibition in H9c2 cell migration and proliferation was assessed by transwell assay and Edu staining, respectively. Collagen deposition and apoptosis were evaluated by western blot detection of collagen and apoptotic proteins, including Capase3, Bax, and Bcl2. We showed that H2O2 treatment significantly decreased H9c2 cell migration and proliferation while increasing H9c2 cell apoptosis. Inhibition of NEAT1 attenuated the cell apoptosis and alleviated proliferation inhibition induced by hypoxia. Bioinformatics analysis showed that miR-129-5p was the direct target of NEAT1, which was confirmed by luciferase assay. NEAT1 upregulation aggravated apoptosis by downregulating miR-129-5p. In conclusion, we uncovered a novel NEAT1-miR129 axis and its implication in H2O2-induced heart failure. Correspondence author: Ling Qin, Department of Cardiology, The First Hospital of Jilin University, No.71 of Xinmin Street, Changchun City, Jilin Province, 130021, PR. China. Tel: 86 0431-84808227 Email: tx75452@163.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion and acetylated low-density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide By inducing vascular inflammation, trimethylamine-N-oxide (TMAO) is associated with endothelial dysfunction, atherosclerosis, and enhanced risk of cardiovascular diseases in humans. However, the underlying mechanisms are unknown. Expression of several genes related to arteriosclerosis, inflammasomes, and endothelial dysfunction was quantified by PCR following exposure to TMAO. LOX-1, ICAM-1, and NLRP3 were also quantified by western blot, while leukocytic adhesion was examined using fluorescently labeled U937 cells. Scavenger receptors (SRs), adhesion molecules, and other genes associated with atherosclerosis were induced in endothelial cells exposed to TMAO. On the other hand, apigenin, a flavonoid that is abundant in parsley and celery, prevents initial arteriosclerosis events in endothelial cells. Apigenin reversed the effects of TMAO on mRNA expression of LOX-1, SREC, SR-PSOX, NLRP3, ASC, TXNIP, VCAM-1, ICAM-1, and MCP-1, as well as protein expression of LOX-1, the adhesion molecule ICAM-1, and the inflammasome protein NLRP3. Apigenin also suppressed leukocyte adhesion and uptake of acetylated low-density lipoprotein. The data indicate that expression of SRs and adhesion molecules in response to TMAO, along with formation of NLRP3 inflammasomes, may drive endothelial dysfunction via uptake of acetylated LDL and lymphocyte adhesion. Apigenin reverses these effects, implying that it may also prevent arteriosclerosis. Corresponding author: Prof. Kazuo Yamagata Ph.D. Laboratory of Molecular Health Science of Food, Department of Food Bioscience and Biotechnology, College of Bioresource Sciences (NUBS), 1866, Kameino, Fujisawa, Kanagawa 252-8510, Japan. Phone: +81-466-84-3986, Fax: +81-466-84-3986 E-mail: yamagata.kazuo@nihon-u.ac.jp Competing interests; The authors report no conflicts of interest. Kazuo Yamagata; yamagata.kazuo@nihon-u.ac.jp, Kazuki Hashiguchi;brka14091@g.nihon-u.ac.jp, Hiroaki Yamamoto;mt.hiro-7714@ezeb.ne.jp, Motoki Tagami; mtagami@sanraku.or.jp, Funding; Not Availability of data and materials; The data used and/or analyzed during the current study are available from the corresponding author on reasonable request. Author’s contributions; K.Y. and M.T conceived and designed the project; K.Y, H.K, S.K and H.Y. performed experiments; K.S and K.H. performed statistical analysis of the data with inputs from S.K. Consent for publication; Not applicable. Ethics approval and consent to participate; Not applicable. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| In vitro anticoagulant activity of Mikania laevigata: deepening the study of the possible interaction between guaco and anticoagulants Mikania laevigata, popularly known in Brazil as guaco, is widely used for respiratory disorders. As this plant is rich in coumarins, there is evidence of indications that it may cause bleeding and therefore should not be used concomitantly with anticoagulants. The basis of this information is very theoretical, with no clinical evidence of such contraindication. Thus, the aim of this study was to evaluate the in vitro effect of M. laevigata extract on blood coagulation through prothrombin (PT) and activated partial thromboplastin (aPTT) tests, fibrinogen plasma concentration (FPC), and the new thrombin generation test (TGT), which investigate, with high sensibility, hemostatic changes (CAAE 60904316.6.0000.5149), besides evaluating its qualitative micromolecular composition, providing scientific evidence to support the management of patients taking warfarin. Ethanolic extracts of guaco leaves were incubated with a plasma pool of healthy individuals at concentrations of 1.67 mg/ml, 2.26 mg/ml, and 2.86 mg/ml. The presence of flavonoids, tannins, coumarins, and triterpenes was demonstrated by selective reagents in thin layer chromatography. Benzoylgrandifloric acid, cinnamoylgrandifloric acid, o-coumaric acid, coumarin, and quercetin-3-β-glucoside were identified by co-injection in ultra-performance liquid chromatography. The extract at all concentrations prolonged TP and aPPT, and reduced the potential for endogenous thrombin potential (ETP) by TGT. The control plasma had ETP=1465 nM/min and after the addition of M. laevigata extract (2.26 mg/mL), this value was reduced to 1087 nM/min, indicating a lower generation of thrombin. Related to FPC, concentrations of 2.26 mg/mL and 2.86 mg/mL were effective in reducing plasma fibrinogen levels. These results allow us to conclude that the guaco extract demonstrated an anticoagulant effect in vitro, possibly interfering with intrinsic, extrinsic, and common coagulation pathways. A discussion on the contribution of the identified substances to the activity is also present. Corresponding author: Paula Mendonça Leite. Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte, Minas Gerais, Brazil. Tel.: +55 31 3409 6936; Fax: +55 31 3409 6935 E-mail address: paulamleite02@gmail.com (P. M. Leite) ORCIT ID 0000-0002-8499-5791 Disclosures: The authors state no conflict of interest. Funding and Acknowledgements: This work was supported by grants from Pró-Reitoria de Pesquisa from Universidade Federal de Minas Gerais, Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics Committee of the Federal University of Minas Gerais number CAAE 60904316.6.0000.5149) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| The role of YAP/TAZ in energy metabolism in the heart The heart requires a high amount of energy, in the form of adenosine triphosphate (ATP), to maintain its viability and pump function. Anaerobic glycolysis and mitochondrial oxidative phosphorylation are the main metabolic pathways by which ATP is generated, utilizing fatty acids (FAs), glucose, lactate, and ketone bodies as primary substrates. Previous studies have demonstrated that, in response to stress, the heart undergoes alterations in metabolism, ranging from changes in substrate utilization to mitochondrial function, collectively called metabolic remodeling. However, the molecular mechanism mediating metabolic remodeling in the heart remains unclear. Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which are major downstream effectors of the Hippo signaling pathway, play an important role in the regulation of heart size and cellular homeostasis of cardiomyocytes through the regulation of various transcriptional factors under both physiological and pathophysiological conditions. Recent findings in various organs and cell types have revealed that YAP and TAZ play an important role in energy metabolism. Here we summarize what is currently known about YAP/TAZ in the regulation of metabolism of various substrates and mitochondrial function in various organs and cell types and discuss the potential role of YAP/TAZ in mediating metabolic remodeling of the heart during stress and heart failure. Address correspondence to: Junichi Sadoshima, MD, PhD Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, 185 S. Orange Ave., MSB G609, Newark, NJ 07103, USA Phone: +1-973-972-8916 E-mail: sadoshju@njms.rutgers.edu Sources of funding: This work was supported in part by U.S. Public Health Service Grants HL67724, HL91469, HL112330, HL138720, and AG23039 (J.S.), and by the Foundation of Leducq Transatlantic Network of Excellence 15CBD04 (J.S.). T.K. has been supported by a Postdoctoral Fellowship from the Uehara Memorial Foundation. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| Quantitative association between serum/dietary magnesium and cardiovascular disease/coronary heart disease risk: a dose-response meta-analysis of prospective cohort studies Background: The quantitative association between serum/dietary magnesium and cardiovascular disease (CVD) remains unclear. We conducted a dose-response meta-analysis to evaluate the quantitative association between serum/dietary magnesium and CVD, including coronary heart disease (CHD). Methods: PubMed, China National Knowledge Infrastructure, and Web of Science were searched for publications. STATA 12.0 was used to analyze data. We used the random effects model to reduce heterogeneity. Results: Eighteen prospective cohort studies with 544,581 participants and 22,658 CVD cases were included. The follow-up duration was 1-28 years. The pooled relative risk (RR) of CVD for the relatively normal versus lowest serum and dietary magnesium level was 0.64 (95% confidence interval (CI): 0.51-0.80) and 0.90 (95%CI: 0.84-0.96). The pooled RR of CHD for the relatively normal versus lowest serum and dietary magnesium level was 0.70 (95%CI: 0.57-0.85) and 0.86 (95%CI: 0.77-0.94). We noted a significant association between increasing serum magnesium levels (per 0.1 mg/dL increase) and risk of CVD (RR: 0.93, 95%CI: 0.88-0.97) and CHD (RR: 0.90, 95%CI: 0.84-0.96) and between dietary magnesium levels (per 100 mg/day increase) and risk of CVD (RR: 0.90, 95%CI: 0.83-0.96) and CHD (RR: 0.92, 95%CI: 0.82-0.98). Serum/dietary Mg level comparisons presented a 7-10% decrease in CVD/CHD risk. The dose-response meta-analyses showed linear relationships between serum magnesium and CVD (Pnonlinearity=0.833) or CHD (Pnonlinearity=0.193) and dietary magnesium and CVD (Pnonlinearity=0.463) or CHD (Pnonlinearity=0.440). Conclusions: Increasing dietary magnesium or serum magnesium level is linearly and inversely associated with the risk of total CVD and CHD events. Correspondence to: Dr. Meimi Zhao, Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China. Tel: (+86)18900910371, E-mail: mmzhao@cmu.edu.cn Conflicts of interest: The authors have no conflict of interest to report. Funding: This study was supported by the National Natural Science Foundation of China (No. 31500930) and the Program for Liaoning Innovation Research Team in University. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| Up-regulating microRNA-203 alleviates myocardial remodeling and cell apoptosis through down-regulating PTP1B in rats with myocardial infarction Myocardial infarction (MI) is one of cardiovascular diseases with high incidence and mortality. MicroRNAs (miRNAs), as post-transcriptional regulators of genes, are involved in many diseases, including cardiovascular diseases. The aim of present study was to determine whether miR-203 was functional in MI therapy and how it worked. Left anterior descending artery ligation and hypoxia/reoxygenation (H/R) treatment were respectively performed to obtain MI rats and hypoxia-injured H9c2 cells. Western blot and qRT-PCR were used to determine protein levels and mRNA of relevant genes, respectively. Lentivirus-mediated over-expression of miR-203 was performed to study the miR-203 functions on left ventricular remodeling, infarct size and cardiomyocyte apoptosis. Compared with the sham group, miR-203 levels were significantly decreased in MI and H/R groups. However, over-expressing miR-203 greatly improved the cardiac function, reduced infarct size in rats after MI, as well as weakened infarction-induced apoptosis by increasing Bcl-2 and reducing decreasing Bax, cleaved caspase-3 and cleaved caspase-9. In addition, PTP1B was proved as a target of miR-203 in cardiomyocytes, and it was negatively regulated by miR-203. Further experiments indicated that PTP1B over-expression could remarkably inhibit miR-203-mediated anti-apoptosis of cardiomyocytes, and alleviate protective effects of miR-203 on mitochondria after H/R treatment. Altogether, miR-203 prevented infarction-induced apoptosis by regulating PTP1B, including reducing pro-apoptosis proteins, inactivating caspase pathway and protecting mitochondria. In conclusion, miR-203 had abilities to alleviate MI-caused injury on myocardium tissues and reduce mitochondria-mediated apoptosis, which might be a potential target used for MI therapy. Correspondence author at:Zhenfei Chen, Department of Cardiovascular, the Second People Hospital of He Fei, No. 246 Heping Street, Hefei City, Anhui Province, 230021,PR. China htluyti21784408@126.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
| The cardioprotective effects of Atorvastatin are mediated via PPARγ in Paraquat-exposed rats Background: paraquat poisoning is one of leading intoxication worldwide without an effective antidote and treatment protocol. Among the other organs, cardiotoxicity of paraquat has been frequently reported. Aim: The protective effects of atorvastatin (STN) on paraquat-induced cardiotoxicity and the role of peroxisome proliferator-activated receptors γ in the mediation of STN effects were investigated. Methods: Forty-two male Wistar rats were aliquoted into control or test groups. The animals in test groups in addition of paraquat, received saline normal (PQ), pioglitazone (PGT), atorvastatin (STN), PGT + STN, PGT + GW9662 and/or STN + GW9662 for 14 days. Results: PGT and STN lowered lipid peroxidation rate, nitric oxide concentration and activity of myeloperoxidase and CK/MB in the heart. PGT and STN protected from thiol molecules reduction and PQ-induced histopathological injuries. STN regulated the PQ-induced up-regulation of COX-II expression in the heart. All STN-related protective effects were reversed by GW9662 as PPARγ antagonist. Conclusion: These data suggest a cardioprotective effect for STN against the PQ-induced inflammation and oxidative stress. The pharmacologic approach of these findings indicate that STN via PPARγ pathway lowered the PQ-induced cardiotoxicity. Corresponding to: Hassan Malekinejad, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran Hassanmalekinejad@yahoo.com Tel: +989141496558 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. |
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