Londono, Juan E. Camacho and Tian, Qinghai and Hammer, Karin and Schroeder, Laura and Londono, Julia Camacho and Reil, Jan C. and He, Tao and Oberhofer, Martin and Mannebach, Stefanie and Mathar, Ilka and Philipp, Stephan E. and Tabellion, Wiebke and Schweda, Frank and Dietrich, Alexander and Kaestner, Lars and Laufs, Ulrich and Birnbaumer, Lutz and Flockerzi, Veit and Freichel, Marc and Lipp, Peter (2015) A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. EUROPEAN HEART JOURNAL, 36 (33). pp. 2257-2266. ISSN 0195-668X, 1522-9645
Full text not available from this repository. (Request a copy)Abstract
Aims Pathological cardiac hypertrophy is a major predictor for the development of cardiac diseases. Neuroendocrine factors such as norepinephrine and angiotensin II trigger Ca2+-dependent processes leading to cell growth and cardiac hypertrophy. Here, we report the identification of a constitutively active background Ca2+ entry (BGCE) pathway that is not affected by inhibition of voltage-gated Ca2+ channels but critically depends on the presence of TRPC1 and TRPC4 proteins, members of the TRP family of cation channels. It fine-tunes Ca2+ cycling in beating cardiomyocytes under basal conditions and during neurohumoral stimulation. Suppression of BGCE protects against development of maladaptive cardiac remodelling without evidence for alterations in cardiac or extra-cardiac functions and may represent a potential new therapeutic strategy to attenuate the pathogenesis of associated diseases.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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RECEPTOR POTENTIAL CHANNELS; HEART-FAILURE; MOUSE HEART; HYPERTROPHY; MICE; ACTIVATION; TRPC; EXPRESSION; MYOCYTES; PROTEIN; Calcium; Ion channels; Cardiac remodelling; Background Ca2+ entry; TRPC1/TRPC4 |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Frank Schweda |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Jun 2019 13:08 |
| Last Modified: | 12 Jun 2019 13:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4911 |
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