TRPC3 Overexpression Promotes AngiotensinII Induced Cardiac Dysfunction

Abstract

TRPC3 was recently suggested as a player in the development of cardiac hypertrophy. Little is known about the direct proarrhythmogenic role for TRPC3. Here we examined the involvement of TRPC3 in cardiac actions of AngiotensinII (AngII), a pathophysiologically relevant mediator and activator of GPCR/Gq/TRPC3 signaling, using a TRPC3 transgenic mouse model. A comparison of AngII actions in the isolated Langendorff perfused heart of TRPC3+/- (N=5) and wild-type (WT) mice (N=5) revealed that TRPC3 overexpression strongly promoted the impairment of cardiac functions by AngII. Administration of AngII (100nM) reduced left ventricular pressure (LVP) within 2 min to 64 %, + dP/dt to 50 % and - dP/dt to 55 % of control in TRPC3+/- hearts, while these functions remained largely unaffected in WT hearts. Simultaneously ECG recordings demonstrated AngII-induced episodes of acute arrhythmogenicity with ventricular ectopies in all TRPC3+/- hearts (N=6), whereas rhythm of WT hearts (N=6) remained unaffected. Changes in Ca2+ transients and sarcomere shortening were analyzed in isolated ventricular myocytes. AngII (100nM) induced a rise in the diastolic Ca2+ level, which was accompanied by irregular contractions in TRPC3 overexpressing but not in WT myocytes. Our results demonstrate that AngII modulation of cardiac functions is strictly dependent on TRPC3 expression and suggest a key role of TRPC channels in AngII-mediated arrhythmogenicity. Supporteded by FWF, DK-MCD