Abstract 10832: Transient Receptor Potential Melastatin 7 (TRPM7) Contributes to Myocardial Ischemic Injury

Introduction: Ischemic heart disease is the leading cause of death in the USA. Despite the progress of interventional coronary reperfusion strategies, myocardial ischemia reperfusion (I/R) injury remains a substantial challenge for treatment. TRPM7 is a Ca 2+ -permeable nonselective channel which plays an important role in cardiogenesis and atrial fibrillation. However the role of TRPM7 in pathogenesis of myocardial I/R is unknown. Hypothesis: TRPM7 contributes to myocardial I/R injury. Methods: TRPM7 knockout mice (M7KO) and Cre - control littermates (WT) mice were exposed to 45 min ischemia or sham procedure followed by 24 hrs of reperfusion (n=8 to 12/group). Heart function was evaluated by echocardiograph, and in vitro assays were used for mechanistic investigation. Results: We found that TRPM7 expression was upregulated in I/R injury WT mouse hearts. Global M7KO (gM7KO) improved heart performance via increasing the ejection fraction and fraction shortening by 29.1 ± 4.2 % and 10.8 ± 3.0 % respectively (p<0.05). Trpm7 deletion also reduced the infarct size by 31.1 ± 1.2 % in comparison with WT mice (P<0.05). Myocytes specific knockout (mM7KO) exhibited similar protective effect against I/R injury. Moreover, deletion of Trpm7 significantly reduced tunnel positive cells, suggesting that upregulated TRPM7 in WT mice contributed to myocyte apoptosis in I/R injury. Interestingly, deletion of Trpm7 also significantly reduced the protein level of NLRP3, cleaved-caspase-1 and mature IL-1β after I/R injury (p<0.05), indicating that TRPM7 contributed to pyroptosis during I/R injury. Consistent with the increased IL-1β level induced by I/R injury in WT mice, the cleaved N-terminal Gasdermin D (N-GSDMD) level was also increased in WT I/R injury hearts versus sham control hearts. Deletion of Trpm7 significantly attenuated the increase of the cleaved N-GSDMD level induced by I/R injury (p<0.05). Conclusions: Trpm7 deletion in cardiac myocytes protects mice against myocardial ischemic injury. This is the first study to demonstrate the important role of TRPM7 in I/R injury through the mechanisms of activation of both apoptosis and pyroptosis. Our results suggest that TRPM7 may serve as a novel therapeutic target for myocardial ischemia/reperfusion injury.