A background Ca2+entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling
Year: 2015
Type: article
Abstract: 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 Ca(2+) signalling in cardiomyocytes. TRPC proteins form agonist-induced cation channels, but their functional role for Ca(2+) homeostasis in cardiomyocytes during fast cytosolic Ca(2+) 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 Mn(2+)-quench microfluorimetry, we identified a background Ca(2+) 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 Ca(2+) 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 Ca(2+)-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 Ca(2+) 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.
Source: European Heart Journal
Authors: Juan E. Camacho Londoño, Qinghai Tian, Karin Hammer, Laura Schröder, Julia Camacho Londoño, Jan C. Reil, Tao He, Martin Oberhofer, Stefanie Mannebach, Ilka Mathar, Stephan E. Philipp, Wiebke Tabellion, Frank Schweda, Alexander Dietrich, Lars Kaestner, Ulrich Laufs, Lutz Birnbaumer, Veit Flockerzi, Marc Freichel, Peter Lipp
Institutions: Heidelberg University, German Centre for Cardiovascular Research, Universitätsklinikum des Saarlandes, Saarland University, Tongji Hospital, Huazhong University of Science and Technology, University of Regensburg, Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, National Institute of Environmental Health Sciences
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2109449142