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Eur Heart J. 2015 Sep 1;36(33):2257-66. doi: 10.1093/eurheartj/ehv250. Epub 2015 Jun 11.

A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling.

Author information

1
Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
2
Institut für Molekulare Zellbiologie, 66421 Homburg, Germany.
3
Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
4
Innere Medizin III Universität des Saarlandes, 66421 Homburg, Germany.
5
DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany Research Unit Cardiac Epigenetics, Department of Cardiology, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
6
Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany.
7
Institut für Physiologie, Universität Regensburg, 93053 Regensburg, Germany.
8
Walther-Straub-Institut für Pharmakologie und Toxikologie, LMU, 80336 München, Germany.
9
Transmembrane Signaling Group, NIEHS, PO Box 12233, NC 27709, USA.
10
Pharmakologisches Institut, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany Experimentelle und Klinische Pharmakologie und Toxikologie, 66421 Homburg, Germany DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany marc.freichel@pharma.uni-heidelberg.de peter.lipp@uniklinikum-saarland.de.
11
Institut für Molekulare Zellbiologie, 66421 Homburg, Germany marc.freichel@pharma.uni-heidelberg.de peter.lipp@uniklinikum-saarland.de.

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.

KEYWORDS:

Background Ca2+ entry; Calcium; Cardiac remodelling; Ion channels; TRPC1/TRPC4

PMID:
26069213
PMCID:
PMC4554959
DOI:
10.1093/eurheartj/ehv250
[Indexed for MEDLINE]
Free PMC Article

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