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      Resveratrol attenuates angiotensin II-induced cellular hypertrophy through the inhibition of CYP1B1 and the cardiotoxic mid-chain HETE metabolites

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          Abstract

          Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. Resveratrol is commercially available polyphenol that exerts beneficial effects in wide array of cardiovascular diseases including cardiac hypertrophy, myocardial infarction and heart failure. Nevertheless, the underlying mechanisms responsible for these effects are not fully elucidated. Since resveratrol is a well-known CYP1B1 inhibitor, the purpose of this study is to test whether resveratrol attenuates angiotensin II (Ang II)-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. RL-14 and H9c2 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 2, 10 or 50 μM resveratrol for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography–mass spectrometry (LC/MS). Hypertrophic markers and CYP1B1 gene expression and protein levels were measured using real-time PCR and Western blot analysis, respectively. Our results demonstrated that resveratrol, at concentrations of 10 and 50 μM, was able to attenuate Ang-II-induced cellular hypertrophy as evidenced by substantial inhibition of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide. Ang II significantly induced the protein expression of CYP1B1 and increased the metabolite formation rate of its associated mid-chain HETEs. Interestingly, the protective effect of resveratrol was associated with a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Our results provided the first evidence that resveratrol protects against Ang II-induced cellular hypertrophy, at least in part, through CYP1B1/mid-chain HETEs-dependent mechanism.

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          Resveratrol and Cardiovascular Diseases

          The increased incidence of cardiovascular diseases (CVDs) has stimulated research for substances that could improve cardiovascular health. Among them, resveratrol (RES), a polyphenolic compound notably present in grapes and red wine, has been involved in the “French paradox”. RES is known for its antioxidant and anti-inflammatory properties and for its ability to upregulate endothelial NO synthase (eNOS). RES was able to scavenge •OH/O2 •− and peroxyl radicals, which can limit the lipid peroxidation processes. Moreover, in bovine aortic endothelial cells (BAEC) under glucose-induced oxidative stress, RES restored the activity of dimethylargininedimethylaminohydrolase (DDAH), an enzyme that degrades an endogenous inhibitor of eNOS named asymmetric dimethylarginine (ADMA). Thus, RES could improve •NO availability and decrease the endothelial dysfunction observed in diabetes. Preclinical studies have made it possible to identify molecular targets (SIRT-1, AMPK, Nrf2, NFκB…); however, there are limited human clinical trials, and difficulties in the interpretation of results arise from the use of high-dose RES supplements in research studies, whereas low RES concentrations are present in red wine. The discussions on potential beneficial effects of RES in CVDs (atherosclerosis, hypertension, stroke, myocardial infarction, heart failure) should compare the results of preclinical studies with those of clinical trials.
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            Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease.

            Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post-infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD).
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              Heart Failure: Diagnosis, Management and Utilization

              Despite the advancement in medicine, management of heart failure (HF), which usually presents as a disease syndrome, has been a challenge to healthcare providers. This is reflected by the relatively higher rate of readmissions along with increased mortality and morbidity associated with HF. In this review article, we first provide a general overview of types of HF pathogenesis and diagnostic features of HF including the crucial role of exercise in determining the severity of heart failure, the efficacy of therapeutic strategies and the morbidity/mortality of HF. We then discuss the quality control measures to prevent the growing readmission rates for HF. We also attempt to elucidate published and ongoing clinical trials for HF in an effort to evaluate the standard and novel therapeutic approaches, including stem cell and gene therapies, to reduce the morbidity and mortality. Finally, we discuss the appropriate utilization/documentation and medical coding based on the severity of the HF alone and with minor and major co-morbidities. We consider that this review provides an extensive overview of the HF in terms of disease pathophysiology, management and documentation for the general readers, as well as for the clinicians/physicians/hospitalists.
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                Author and article information

                Contributors
                aelkadi@ualberta.ca
                Journal
                Mol Cell Biochem
                Mol. Cell. Biochem
                Molecular and Cellular Biochemistry
                Springer US (New York )
                0300-8177
                1573-4919
                12 June 2020
                : 1-12
                Affiliations
                [1 ]GRID grid.17089.37, Faculty of Pharmacy and Pharmaceutical Sciences, , University of Alberta, ; Edmonton, AB Canada
                [2 ]GRID grid.17089.37, Faculty of Pharmacy & Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, , University of Alberta, ; Edmonton, AB T6G 2E1 Canada
                Author information
                http://orcid.org/0000-0002-8692-0400
                Article
                3777
                10.1007/s11010-020-03777-9
                7291180
                32533462
                8f13b479-14e6-4261-9302-7b01c5eaf7a7
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 28 February 2020
                : 31 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: Grant 106665
                Award Recipient :
                Categories
                Article

                Biochemistry
                resveratrol,cardiac hypertrophy,cyp1b1,mid-chain hetes
                Biochemistry
                resveratrol, cardiac hypertrophy, cyp1b1, mid-chain hetes

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