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      Tongguan Capsule Mitigates Post-myocardial Infarction Remodeling by Promoting Autophagy and Inhibiting Apoptosis: Role of Sirt1

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          Abstract

          Left ventricular (LV) adverse remodeling and the concomitant functional deterioration contributes to the poor prognosis of patients with myocardial infarction (MI). Thus, a more effective treatment strategy is needed. Tongguan capsule (TGC), a patented Chinese medicine, has been shown to be cardioprotective in both humans and animals following ischemic injury, although its precise mechanism remains unclear. To investigate whether TGC can improve cardiac remodeling in the post-infarct heart, adult C57/BL6 mice underwent coronary artery ligation and were administered TGC or vehicle (saline) for 6 weeks. The results demonstrated that the TGC group showed significant improvement in survival ratio and cardiac function and structure as compared to the vehicle group. Histological and western blot analyses revealed decreased cellular inflammation and apoptosis in cardiomyocytes of the TGC group. Furthermore, TGC upregulated the Atg5 expression and LC3II-to-LC3I ratio but downregulated autophagy adaptor p62 expression, suggesting that TGC led to increased autophagic flux. Interestingly, with the administration of 3-methyladenine, an autophagy inhibitor, in conjunction with TGC, the aforesaid effects significantly decreased. Further mechanistic studies revealed that TGC increased silent information regulator 1 (Sirt1) expression to reduce the phosphorylation of the mammalian target of rapamycin and its downstream effectors P70S6K and 4EBP1. Moreover, the induction of Sirt1 by TGC was inhibited by the specific inhibitor EX527. In the presence of EX527, TGC-induced autophagy-specific proteins were downregulated, while apoptotic and inflammatory factors were upregulated. In summary, our results demonstrate that TGC improved cardiac remodeling in a murine model of MI by preventing cardiomyocyte inflammation and apoptosis but enhancing autophagy through Sirt1 activation.

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          Most cited references 48

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          Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

          Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
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            Life and death partners: apoptosis, autophagy and the cross-talk between them.

            It is not surprising that the demise of a cell is a complex well-controlled process. Apoptosis, the first genetically programmed death process identified, has been extensively studied and its contribution to the pathogenesis of disease well documented. Yet, apoptosis does not function alone to determine a cell's fate. More recently, autophagy, a process in which de novo-formed membrane-enclosed vesicles engulf and consume cellular components, has been shown to engage in a complex interplay with apoptosis. In some cellular settings, it can serve as a cell survival pathway, suppressing apoptosis, and in others, it can lead to death itself, either in collaboration with apoptosis or as a back-up mechanism when the former is defective. The molecular regulators of both pathways are inter-connected; numerous death stimuli are capable of activating either pathway, and both pathways share several genes that are critical for their respective execution. The cross-talk between apoptosis and autophagy is therefore quite complex, and sometimes contradictory, but surely critical to the overall fate of the cell. Furthermore, the cross-talk is a key factor in the outcome of death-related pathologies such as cancer, its development and treatment.
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              Autophagy in metazoans: cell survival in the land of plenty.

              Cells require a constant supply of macromolecular precursors and oxidizable substrates to maintain viability. Unicellular eukaryotes lack the ability to regulate nutrient concentrations in their extracellular environment. So when environmental nutrients are depleted, these organisms catabolize existing cytoplasmic components to support ATP production to maintain survival, a process known as autophagy. By contrast, the environment of metazoans normally contains abundant extracellular nutrients, but a cell's ability to take up these nutrients is controlled by growth factor signal transduction. Despite evolving the ability to maintain a constant supply of extracellular nutrients, metazoans have retained a complete set of autophagy genes. The physiological relevance of autophagy in such species is just beginning to be explored.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                22 May 2018
                2018
                : 9
                Affiliations
                1Key Discipline of Integrated Chinese and Western Medicine, Second Clinical College, Guangzhou University of Chinese Medicine , Guangzhou, China
                2Department of Critical Care Medicine, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, China
                3Cardiovascular Institute, Stanford University School of Medicine , Stanford, CA, United States
                Author notes

                Edited by: Jing-Yan Han, Peking University, China

                Reviewed by: Houzao Chen, University of Chinese Academy of Sciences, China; Huabo Su, Augusta University, United States

                *Correspondence: Minzhou Zhang, minzhouzhang@ 123456aliyun.com

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.00589
                5972280
                Copyright © 2018 Mao, Chen, Li, Guo and Zhang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 57, Pages: 15, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81703877
                Categories
                Physiology
                Original Research

                Anatomy & Physiology

                cardiac remodeling, tongguan capsules, autophagy, apoptosis, sirt1

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