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Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel
Tian Jia1, Xiaozhi Wang2, Yiqun Tang3
1State Key Laboratory of Natural Medicines, Department of Life Sciences and Technology, 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.
Insights
Sacubitril, a component of sacubitril/valsartan, treats cardiac fibrosis by inhibiting the TRPM7 channel. This action reduces fibroblast activation and cardiomyocyte programmed cell death (PCD), improving heart function.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Cellular Physiology
Background:
- Cardiac fibrosis, a major cause of heart failure, involves cardiomyocyte programmed cell death (PCD) and fibroblast activation.
- Aberrant calcium (Ca2+) influx through the TRPM7 channel is implicated in these pathological processes.
- TRPM7 is a key regulator of cardiac fibrosis.
Purpose of the Study:
- To elucidate the mechanism by which sacubitril, a component of sacubitril/valsartan, treats cardiac fibrosis.
- To investigate the role of TRPM7 channel in the anti-fibrotic effects of sacubitril.
Main Methods:
- In vivo studies using isoproterenol (ISO) to induce cardiac fibrosis and dysfunction.
- In vitro studies on fibroblasts and cardiomyocytes.
- Assessment of TRPM7 channel activity and protein expression.
- Evaluation of transforming growth factor-β 1 (TGF-β1) and hypoxia-induced effects.
Main Results:
- Sacubitril/valsartan ameliorated cardiac dysfunction and reduced fibrosis in vivo.
- LBQ657, sacubitril's metabolite, attenuated TGF-β1-induced cardiac fibrosis by blocking TRPM7 channel activity.
- LBQ657 reduced hypoxia-induced cardiomyocyte PCD by suppressing TRPM7-regulated Ca2+ influx.
Conclusions:
- Sacubitril exerts anti-fibrotic effects by inhibiting the TRPM7 channel in both fibroblasts and cardiomyocytes.
- Targeting TRPM7 channel represents a potential therapeutic strategy for cardiac fibrosis and heart failure.
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