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      Pharmacological Modulation of Cardiac Remodeling after Myocardial Infarction

      review-article
      1 , 2 , 1 , 1 , 3 ,
      Oxidative Medicine and Cellular Longevity
      Hindawi

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          Abstract

          Cardiac remodeling describes a series of structural and functional changes in the heart after myocardial infarction (MI). Adverse post-MI cardiac remodeling directly jeopardizes the recovery of cardiac functions and the survival rate in MI patients. Several classes of drugs are proven to be useful to reduce the mortality of MI patients. However, it is an ongoing challenge to prevent the adverse effects of cardiac remodeling. The present review aims to identify the pharmacological therapies from the existing clinical drugs for the treatment of adverse post-MI cardiac remodeling. Post-MI cardiac remodeling is a complex process involving ischemia/reperfusion, inflammation, cell death, and deposition of extracellular matrix (ECM). Thus, the present review included two parts: (1) to examine the basic pathophysiology in the cardiovascular system and the molecular basis of cardiac remodeling and (2) to identify the pathological aspects of cardiac remodeling and the potential of the existing pharmacotherapies. Ultimately, the present review highlights drug repositioning as a strategy to discover effective therapies from the existing drugs against post-MI cardiac remodeling.

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          Most cited references138

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          Alternative activation of macrophages: mechanism and functions.

          The concept of an alternative pathway of macrophage activation has stimulated interest in its definition, mechanism, and functional significance in homeostasis and disease. We assess recent research in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment. The stage is now set to gain deeper insights into the role of alternatively activated macrophages in immunobiology. Copyright 2010 Elsevier Inc. All rights reserved.
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            The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis.

            In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
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              Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

              Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2020
                30 December 2020
                : 2020
                : 8815349
                Affiliations
                1School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China
                2Zhujiang Hospital, Southern Medical University, 253 Industrial Road, Guangzhou, Guangdong Province, China
                3Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
                Author notes

                Academic Editor: Xue Han

                Author information
                https://orcid.org/0000-0002-3709-7315
                Article
                10.1155/2020/8815349
                7790555
                33488941
                8df634d2-055f-4d16-8e05-3f729db65a28
                Copyright © 2020 Wei Zhao et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 September 2020
                : 13 November 2020
                : 21 December 2020
                Funding
                Funded by: Hong Kong Scholars Program
                Award ID: XJ2019055
                Funded by: Midstream Research Programme for Universities
                Award ID: 053/18X
                Funded by: Health and Medical Research Fund
                Award ID: 17181231
                Award ID: 16171751
                Funded by: National Natural Science Foundation of China
                Award ID: 21778046
                Award ID: 81703726
                Award ID: 81701464
                Funded by: General Research Fund
                Award ID: 17119619
                Award ID: 17100317
                Award ID: 17146216
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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