Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel.

Abstract

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca2+ influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca2+ permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) in vivo. We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD via suppression of Ca2+ influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.

• Authors: Tian Jia, Xiaozhi Wang, Yiqun Tang, Wenying Yu, Chenhui Li, Shufang Cui, Juanjuan Zhu, Wei Meng, Chen Wang, Quanyi Wang
• Journal: Frontiers in cell and developmental biology (Front Cell Dev Biol) Vol. 9 Pg. 760035 ( 2021) ISSN: 2296-634X [Print] Switzerland
• PMID: 34778271 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Jia, Wang, Tang, Yu, Li, Cui, Zhu, Meng, Wang and Wang.