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Aims: After summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca 2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling., Methods and Results: Mn 2+ -quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (-51.4%) or after one week of transverse aortic constriction (TAC; -73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts., Conclusions: Deletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

TRPC proteins form cation conducting channels regulated by different stimuli and are regulators of the cellular calcium homeostasis. TRPC are expressed in cardiac cells including cardiac fibroblasts (CFs) and have been implicated in the development of pathological cardiac remodeling including fibrosis. Using Ca 2+ imaging and several compound TRPC knockout mouse lines we analyzed the involvement of TRPC proteins for the angiotensin II (AngII)-induced changes in Ca 2+ homeostasis in CFs isolated from adult mice. Using qPCR we detected transcripts of all Trpc genes in CFs; Trpc1 , Trpc3 and Trpc4 being the most abundant ones. We show that the AngII-induced Ca 2+ entry but also Ca 2+ release from intracellular stores are critically dependent on the density of CFs in culture and are inversely correlated with the expression of the myofibroblast marker α-smooth muscle actin. Our Ca 2+ measurements depict that the AngII- and thrombin-induced Ca 2+ transients, and the AngII-induced Ca 2+ entry and Ca 2+ release are not affected in CFs isolated from mice lacking all seven TRPC proteins (TRPC-hepta KO) compared to control cells. However, pre-incubation with GSK7975A (10 µM), which sufficiently inhibits CRAC channels in other cells, abolished AngII-induced Ca 2+ entry. Consequently, we conclude the dispensability of the TRPC channels for the acute neurohumoral Ca 2+ signaling evoked by AngII in isolated CFs and suggest the contribution of members of the Orai channel family as molecular constituents responsible for this pathophysiologically important Ca 2+ entry pathway., Competing Interests: The authors declare no conflict of interest.

Rationale: The Trpm4 gene has recently been associated with several disorders, including cardiac conduction diseases and Brugada syndrome. Transient receptor potential member 4 (TRPM4) proteins constitute Ca2+ -activated, but Ca2+ -impermeable, nonselective cation channels and are expressed both in atrial and in ventricular cardiomyocytes. The physiological function of TRPM4 in the heart remains, however, incompletely understood., Objective: To establish the role of TRPM4 in cardiac muscle function., Methods and Results: We used TRPM4 knockout mice and performed patch-clamp experiments, membrane potential measurements, microfluorometry, contractility measurements, and in vivo pressure-volume loop analysis. We demonstrate that TRPM4 proteins are functionally present in mouse ventricular myocytes and are activated on Ca2+ -induced Ca2+ release. In Trpm4(-/-) mice, cardiac muscle displays an increased β-adrenergic inotropic response both in vitro and in vivo. Measurements of action potential duration show a significantly decreased time for 50% and 90% repolarization in Trpm4(-/-) ventricular myocytes. We provide evidence that this change in action potential shape leads to an increased driving force for the L-type Ca2+ current during the action potential, which explains the altered contractility of the heart muscle., Conclusions: Our results show that functional TRPM4 proteins are novel determinants of the inotropic effect of β-adrenergic stimulation on the ventricular heart muscle.