TRPM7 Deficiency Protects Against Myocardial Ischemia-Reperfusion Injury by Regulating Intracellular Zn²⁺ Homeostasis

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 Zn²⁺ from unique intracellular TRPM7 vesicles. However, the pathophysiological role of intracellular TRPM7 remains poorly understood.

TRPM7 expression was determined in hearts from patients with ischemic heart failure and I/R-injured mice. Global (gTrpm7^-/-), 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 neonatal and adult mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with patch-clamp, Zn²⁺ imaging, and molecular biology techniques. An inducible TRPM7 channel-dead (TRPM7-E1047K) knock-in mouse model was generated to elucidate the functional domains of TRPM7 for therapeutic strategies.

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 cardiomyocytes and hiPSC-CMs, we revealed that Zn²⁺ 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 an 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.

TRPM7-mediated intracellular Zn²⁺ 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.