Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel

Tian Jia; Xiaozhi Wang; Yiqun Tang; Wenying Yu; Chenhui Li; Shufang Cui; Juanjuan Zhu; Wei Meng; Chen Wang; Quanyi Wang

doi:10.3389/fcell.2021.760035

Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel

Front Cell Dev Biol. 2021 Oct 29:9:760035. doi: 10.3389/fcell.2021.760035. eCollection 2021.

Authors

Tian Jia¹, Xiaozhi Wang², Yiqun Tang³, Wenying Yu⁴, Chenhui Li¹, Shufang Cui¹, Juanjuan Zhu¹, Wei Meng¹, Chen Wang¹, Quanyi Wang¹

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Life Sciences and Technology, China Pharmaceutical University, Nanjing, China.
² Department of Cardiology, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.
³ Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
⁴ State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, China.

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.

Keywords: Ca2+ influx; PCD; TRPM7; cardiac fibrosis; sacubitril.