A background Ca 2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling

Aims: Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. It is associated with chronic neurohumoral stimulation and with altered cardiac Ca2+ signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca2+ homeostasis in cardiomyocytes during fast cytosolic Ca2+ cycling and neurohumoral stimulation leading to hypertrophy is unknown. Methods and results: In a systematic analysis of multiple knockout mice using fluorescence imaging of electrically paced adult ventricular cardiomyocytes and Mn2+-quench microfluorimetry, we identified a background Ca2+ entry (BGCE) pathway that critically depends on TRPC1/C4 proteins but not others such as TRPC3/C6. Reduction of BGCE in TRPC1/C4-deficient cardiomyocytes lowers diastolic and systolic Ca2+ concentrations both, under basal conditions and under neurohumoral stimulation without affecting cardiac contractility measured in isolated hearts and in vivo. Neurohumoral-induced cardiac hypertrophy as well as the expression of foetal genes (ANP, BNP) and genes regulated by Ca2+-dependent signalling (RCAN1-4, myomaxin) was reduced in TRPC1/C4 knockout (DKO), but not in TRPC1- or TRPC4-single knockout mice. Pressure overload-induced hypertrophy and interstitial fibrosis were both ameliorated in TRPC1/C4-DKO mice, whereas they did not show alterations in other cardiovascular parameters contributing to systemic neurohumoral-induced hypertrophy such as renin secretion and blood pressure. Conclusions: The constitutively active TRPC1/C4-dependent BGCE fine-tunes Ca2+ cycling in beating adult cardiomyocytes. TRPC1/C4-gene inactivation protects against development of maladaptive cardiac remodelling without altering cardiac or extracardiac functions contributing to this pathogenesis.Fil: Camacho Londoño, Juan E.. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; AlemaniaFil: Tian, Qinghai. Institut fur Molekulare Zellbiologie; AlemaniaFil: Hammer, Karin. Institut fur Molekulare Zellbiologie; AlemaniaFil: Schröder, Laura. Institut fur Molekulare Zellbiologie; AlemaniaFil: Camacho Londoño, Julia. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Reil, Jan C.. Universitat des Saarlandes; AlemaniaFil: He, Tao. German Centre for Cardiovascular Research; Alemania. Research Unit Cardiac Epigenetics; Alemania. Tongji Hospital; ChinaFil: Oberhofer, Martin. Institut fur Molekulare Zellbiologie; AlemaniaFil: Mannebach, Stefanie. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Mathar, Ilka. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Philipp, Stephan E.. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Tabellion, Wiebke. Institut fur Molekulare Zellbiologie; AlemaniaFil: Schweda, Frank. Universitat Regensburg; AlemaniaFil: Dietrich, Alexander. Walther-Straub-Institut fur Pharmakologie und Toxikologie; AlemaniaFil: Kaestner, Lars. Institut fur Molekulare Zellbiologie; AlemaniaFil: Laufs, Ulrich. Universitat des Saarlandes; AlemaniaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Transmembrane Signaling Group; AlemaniaFil: Flockerzi, Veit. Experimentelle und Klinische Pharmakologie und Toxikologie; AlemaniaFil: Freichel, Marc. Pharmakologisches Institut; Alemania. Experimentelle und Klinische Pharmakologie und Toxikologie; Alemania. German Centre for Cardiovascular Research; AlemaniaFil: Lipp, Peter. Institut fur Molekulare Zellbiologie; Alemani