Endoplasmic Reticulum Stress Regulates Cardiomyocyte Apoptosis in Myocardial Fibrosis Development via PERK-Mediated Auto
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Endoplasmic Reticulum Stress Regulates Cardiomyocyte Apoptosis in Myocardial Fibrosis Development via PERK‑Mediated Autophagy Changjiang Zhang1 · Yuanhong Li2 · Jingbo Zhao2 · Ke Su2 · Ke He2 · Yurong Da2 · Hao Xia1
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Endoplasmic reticulum stress (ERS) is involved in a variety of diseases. Recently, it was found that ERS induces not only apoptosis but also autophagy. Previous studies showed that inhibition of autophagy alleviates cell injury. The purpose of our study was to investigate the involvement of the R-like ER kinase (PERK) in ERS-induced autophagy in H9c2 cardiomyoblasts. To address this aim, therefore, H9c2 cells were treated with PERK agonist and inhibitor after establishment of rapamycininduced ERS models in H9c2 cardiomyoblasts. Transmission electron microscopy and immunofluorescence staining were used to detect degrees of ERS-induced autophagy, apoptosis and myocardial fibrosis. Western blotting was employed to detect the levels of total and phosphorylated PERK, light chain 3 (LC3), P62, Caspase3, Bcl2 and Bax. Immunofluorescence staining was used to assess α-SMA density. TGF-β induced H9c2 cardiomyoblasts time-dependently upregulated col I, col III, FN, and LC3 expressions, PERK phosphorylation and α-SMA density, and downregulated P62 level compared with control cells. Treatment with PERK agonist and inhibitor respectively increased and decreased LC3 expression, conversely in P62 level, which is consistent with effect of ERS agonists and inhibitors. And a PERK inhibitor upregulated the expressions of Caspase3 and Bax, and downregulated Bcl2 level, which developed H9c2 cardiomyoblasts. Moreover, siRNA-mediated knockdown of PERK reduced ERS mediated autophagy activity and increased cells apoptosis. On the other hand, elevated autophagy activity could downregulated PERK level. Our finding showed that PERK activity mediates upregulation of ERSinduced autophagy and regulation of cardiomyocyte apoptosis in H9c2 cardiomyoblasts. Keywords H9c2 cells · Endoplasmic reticulum stress · Protein kinase R-like ER kinase · Autophagy · Apoptosis
Introduction Excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation are the etiological factors leading to the advancement of fibrosis or cardiac dysfunction [1]. Myocardial fibrosis occurs from moderate to severe Handling Editor: Dipak K Dube. Yuanhong Li and Changjiang Zhang are equally contributed to this work. * Hao Xia [email protected] 1
Department of Cardiology, Hubei Key Laboratory of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, People’s Republic of China
Department of Cardiovascularology, The Central Hospital of Enshi Autonomous Prefecture, Enshi 445000, China
2
coronary atherosclerotic stenosis, often involving progressive development of heart failure [2]. Upon coronary atherosclerotic lesions, the heart undergoes repair process accompanied by an inflammatory
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