Abstract P1085: Transient Receptor Potential Cation Channel Subfamily M Member 7 Deficiency Prevents Ventricular Tachycardia During Myocardial Ischemia Reperfusion

Abstract

Introduction: Ventricular arrhythmia caused by myocardial ischemia reperfusion (myo-I/R) remain a substantial challenge worldwide. Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a Ca 2+ -permeable channel, and is involved in cardiogenesis and atrial fibrillation. However, the function of TRPM7 in ventricular arrhythmias during myo-I/R is unknown. Hypothesis: We propose that TRPM7 plays a role in ventricular arrhythmias during myo-I/R, therefore deletion of Trpm7 will protect mice against ventricular arrhythmia during myo-I/R. Methods: We used myo-I/R mouse model, in combination with patch-clamp, and various other techniques to investigate the potential role of TRPM7 in myo-I/R injury. Intracardiac programed electrical stimulation was performed to explore the susceptibility to ventricular arrhythmia, and in vitro assays were used for mechanism investigation. Results: We found that myo-I/R can readily induce spontaneous ventricular tachycardia (VT) in WT mice, whereas global Trpm7 deletion ( Trpm7 -/- ) dramatically reduced incidence of VT by 50.0% ( P <0.05, n =10). In the program induced VT, Trpm7 -/- drastically shortened the duration of VT by 153.5 ± 24.0 (s) ( P <0.05, n=10). As TRPM7 is highly expressed in both myocytes and cardiac fibroblast, we established myocyte-specific Trpm7 deletion and fibroblast-specific Trpm7 deletion mice. We found that TRPM7 in myocytes is responsible for VT induced by myo-I/R. To understand the mechanism by which TRPM7 is involved in VT, we evaluated electrphysiological properties of myocytes. The action potentials (AP) duration of ventricular myocytes isolated from WT mice, which significantly shortened after treatment of oxygen glucose deprivation, whereas Trpm7 -/- restored the AP by prolong the duration without influencing amplitude. Whole-cell patch clamp was performed to record L-type Ca 2+ and K + currents with sodium bisulfite treatment. Interestingly, Trpm7 -/- notably normalized the density of K + current back to the normal level when compared to WT myocytes subjected to oxidative stress. Conclusions: Our results indicate that TRPM7 in myocytes is involved in electrical remodeling during myo-I/R. Inhibition of TRPM7 channel function may serve as a potential target for myo-I/R induced ventricular arrhythmias.