TRPM7 Deficiency Protects Against Myocardial Ischemia-Reperfusion Injury by Regulating Intracellular Zn ²⁺ Homeostasis

BACKGROUND: Ischemic heart disease is one of the leading causes of death worldwide. Timely reperfusion is necessary for myocardium salvage but triggers paradoxical cardiomyocyte death and contributes to up to 50% of the final infarct size, known as lethal ischemia/reperfusion (I/R) injury. TRPM7 (transient receptor potential melastatin 7) is a divalent cation–permeable, nonselective channel kinase that can sense oxidative stress and release Zn 2+ from unique intracellular TRPM7 vesicles. However, the pathophysiological role of intracellular TRPM7 remains poorly understood. METHODS: TRPM7 expression was determined in hearts from patients with ischemic heart failure and I/R-injured mice. Global cardiomyocyte-specific ( cmTrpm7 −/− ) and fibroblast-specific ( fibTrpm7 −/− ) Trpm7 knockout mice were used to determine the role of TRPM7 in I/R injury. Mechanistic investigations were conducted in primary neonatal mouse cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes with patch-clamp, Zn 2 + imaging, and molecular biology techniques. A novel inducible TRPM7 channel dead (TRPM7-E1047K) knock-in mouse model was generated to elucidate the functional domains of TRPM7 for therapeutic strategies. RESULTS: We found that TRPM7 was significantly upregulated in myocardium from both patients with ischemic heart failure and I/R-injured mice. Global TRPM7 deficiency markedly reduced infarct size and improved cardiac function after I/R injury. Using cmTrpm7 −/− and fibTrpm7 −/− mice, we demonstrated that TRPM7 deficiency in myocytes rather than in fibroblasts confers protection against I/R injury by inhibiting pyroptosis as evaluated. Furthermore, using mouse primary cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes, we revealed that Zn 2+ release from intracellular TRPM7 vesicles during I/R injury triggers cardiomyocyte death by activating gasdermin-D to release its N-terminal and form the membrane pore. The critical role of intracellular TRPM7 was further supported by the inability of membrane TRPM7 inhibition to protect mice against I/R injury. To elucidate whether the channel or kinase activity of TRPM7 mediates pyroptosis in I/R injury, we generated a new inducible channel-dead TRPM7-E1047K knock-in mouse model. By comparing with kinase-inactive TRPM7 knock-in mice, we uncovered that the channel but not the kinase function of TRPM7 mediates I/R injury. CONCLUSIONS: TRPM7-mediated intracellular Zn 2 + release contributes to myocardial I/R injury by triggering apoptotic and pyroptotic cardiomyocyte death. Given that TRPM7 is highly upregulated in patients with ischemic heart failure, our findings suggest that targeting TRPM7 may represent a novel therapeutic strategy for ischemic heart disease.