Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice

Abstract

ABSTRACTBackgroundTRPM4 is a calcium-activated, voltage-modulated, non-selective ion channel widely expressed in various types of cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linkedTRPM4mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4’s functional significance in cardiac physiology, its exact roles in the heart remain unclear.AimTo investigate the role of TRPM4 in cardiac physiology in a newly generated knockdownTrpm4mouse model.Methods and resultsMale and femaleTrpm4knockdown (Trpm4-/-) and wild-type mice 5- to 12-weeks-old (young) or 24-week-old or more (adult) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, pseudo and intracardiac ECGs, western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild type andTrpm4-/-5- to 12-weeks-old mice of either sex. Above 24 weeks of age, adult maleTrpm4-/-mice showed significantly reduced heart rate and increased heart rate variability. Echocardiography reveals that only adult maleTrpm4-/-mice exhibited slight left ventricular hypertrophic alterations with an alteration of the mitral valve pressure half time, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in maleTrpm4-/-adult mice. Finally, intracardiac ECG recordings showed that the application of 5 µM NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts only.ConclusionsThese results confirm the important role of TRPM4 in the proper structure and electrical function of the heart. It also reveals significant differences between male and female animals that have never been reported before. In addition, the investigation of the effects of NBA on heart function highlights the role of TRPM4 in atrioventricular conduction and provides the first evidence showing the efficacy of this compound on native cardiac tissues.