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      A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction

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          Abstract

          A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure.

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          Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases.

          A growing body of evidence supports the notion that angiotensin II (Ang II), the central product of the renin-angiotensin system, may play a central role not only in the etiology of hypertension but also in the pathophysiology of cardiovascular and renal diseases in humans. In this review, we focus on the role of Ang II in cardiovascular and renal diseases at the molecular and cellular levels and discuss up-to-date evidence concerning the in vitro and in vivo actions of Ang II and the pharmacological effects of angiotensin receptor antagonists in comparison with angiotensin-converting enzyme inhibitors. Ang II, via AT(1) receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances (vasoactive hormones, growth factors, extracellular matrix components, cytokines, etc.), and activates multiple intracellular signaling cascades (mitogen-activated protein kinase cascades, tyrosine kinases, various transcription factors, etc.) in cardiac myocytes and fibroblasts, vascular endothelial and smooth muscle cells, and renal mesangial cells. These actions are supposed to participate in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, atherosclerosis, and glomerulosclerosis. Furthermore, in vivo recent evidence suggest that the activation of mitogen-activated protein kinases and activator protein-1 by Ang II may play the key role in cardiovascular and renal diseases. However, there are still unresolved questions and controversies on the mechanism of Ang II-mediated cardiovascular and renal diseases.
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            Burden of disease--implications for future research.

            One overall challenge for public health and medicine in the future is to allocate available resources effectively to reduce major causes of disease burden globally and to decrease health disparities between poor and affluent populations. The major risk factors for death and disability worldwide are malnutrition; poor water supply, sanitation, and personal and domestic hygiene; unsafe sexual behavior; tobacco use; alcohol use; occupational hazards; hypertension; physical inactivity; illicit drugs; and air pollution. The challenge for research in the 21st century is to maintain and improve life expectancy and the quality of life that was achieved for most of the world's population during the 20th century.
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              Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window.

              The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-MI.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                07 March 2017
                2017
                : 7
                : 43920
                Affiliations
                [1 ]Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences , Tokyo, Japan
                [2 ]Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences , Tokyo, Japan
                [3 ]Department of Advanced Clinical Science and Therapeutics, The University of Tokyo, Graduate School of Medicine , Tokyo, Japan
                [4 ]Department of Neurology, Osaka University, Graduate School of Medicine , Osaka, Japan
                [5 ]Department of Health Development and Medicine, Osaka University, Graduate School of Medicine , Osaka, Japan
                [6 ]Department of Cardiovascular Medicine, The University of Tokyo, Graduate School of Medicine , Tokyo, Japan
                [7 ]Department of Clinical Gene Therapy, Osaka University, Graduate School of Medicine , Osaka, Japan.
                Author notes
                Article
                srep43920
                10.1038/srep43920
                5339733
                28266578
                62e44051-da93-48b0-86ab-2b6a44406e8d
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 16 May 2016
                : 01 February 2017
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