Jian-Xun Wang1, Xiao-Jie Zhang1, Qian Li1, Kun Wang1, Yin Wang1, Jian-Qin Jiao1, Chang Feng1, Sun Teng1, Lu-Yu Zhou1, Ying Gong1, Zhi-Xia Zhou1, Jia Liu1, Jian-Ling Wang1, Pei-feng Li2. 1. From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.). 2. From the Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China (J.-X.W., K.W., Y.W., S.T., L.-Y.Z., Y.G., Z.-X.Z., J.L., J.-L.W., P.-f.L.); and State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (X.-J.Z., Q.L., J.-Q.J., C.F.). peifli@qdu.edu.cn.
Abstract
RATIONALE: Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently. OBJECTIVE: The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1- and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD. METHODS AND RESULTS: Our results show that FADD participates in H2O2-induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR-103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouse ischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor-α-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis. CONCLUSIONS: Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR-103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis.
RATIONALE: Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently. OBJECTIVE: The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1- and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD. METHODS AND RESULTS: Our results show that FADD participates in H2O2-induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR-103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouseischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor-α-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis. CONCLUSIONS: Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR-103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis.
Authors: Dominic P Del Re; Dulguun Amgalan; Andreas Linkermann; Qinghang Liu; Richard N Kitsis Journal: Physiol Rev Date: 2019-10-01 Impact factor: 37.312