TRPM4 channel re-expression after myocardial infarction is essential for survival in mice

Introduction: TRPM4 is a Ca2+-activated non selective cation channel involved in conduction disorders. TRPM4 is expressed in sinoatrial and atrial cells but only poorly in ventricles. However, in vitro studies detected this current in cardiac hypertrophy concomitantly with fetal gene re-expression. The aim of our study was to investigate whether TRPM4 plays a functional role in ventricular cardiomyocytes in hypertrophy following Myocardial Infarction (MI). Methods: MI was induced by left coronary artery ligation in Trpm4-gene knock-out (Trpm4-/-) and Trpm4+/+ mice (23 and 12, respectively). Post-MI heart failure was verified using Doppler-echocardiography. Electrocardiograms (ECGs) were recorded by telemetry during 12h. Left Ventricular (LV) cardiomyocytes were isolated 4 weeks after MI. Action Potential (AP) and TRPM4-current were recorded using the patch-clamp technique. The propensity of cells to trigger spontaneous electrical activities was assessed. Store-Operated Ca2+-Entry (SOCE), negatively regulated by TRPM4, was measured using fluorescence microscopy. TRPM4 transcript and protein expression in left ventricle were studied using qPCR and western blot analysis. Results: Kaplan-Meier analysis evidenced a higher mortality rate for Trpm4-/–MI mice when compared with Trpm4+/+-MI animals (56% vs. 91%, P=0.03). Echocardiograms showed increased LV mass (3.85±0.4 vs. 2.49±0.2 mg/g, P=0.009) while fractional shortening was reduced (15.2±1.5 vs. 22.7±2.2, P=0.013) in Trpm4-/–MI vs. Trpm4+/+-MI mice. The number of premature ventricular complexes was increased in Trpm4-/–MI vs. Trpm4+/+-MI mice (57±5 vs. 35±3, P=0.028). Surprisingly, there was no difference in the lengthening of AP in LV myocytes following MI between Trpm4-/- and Trpm4+/+ (APD90: 94.4±23 vs. 88±15 ms, P=0.58, respectively). However, Trpm4-/–MI cells exhibited more EADs and DADs than Trpm4+/+-MI (EADs: 11/25 vs. 6/30, P=0.02; DADs: 8/25 vs. 2/30, P=0.008). Moreover, an increase of Trpm4 transcript was found in Trpm4+/+-MI ventricle, associated with TRPM4 protein presence (western blot) and function (TRPM4 current: 1.28±0.1 vs. 0.01±0.06 pA/pF at +40 mV, P=0.001). This expression correlated to a decrease of SOCE in cardiomyocytes from MI group vs. sham group (P=0.001). Conclusion: Lack of TRPM4 channel re-expression in the LV worsened the deleterious effects of post-MI cardiac remodeling on survival, hypertrophy, heart function, and arrhythmic events. Negative regulation of SOCE, involved in cardiac remodeling, and occurrence of spontaneous cellular arrhythmias suggests that TRPM4 channel plays a critical role in post-MI adaptations.