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Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice

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Abstract

Sustained elevation of intracellular Ca2+ concentration ([Ca2+]i) reprograms cardiovascular cell fate, leading to cellular hypertrophy via Ca2+-calmodulin/calcineurin (Cn)/NFAT activation. Accumulating evidence suggests that transient receptor potential canonical (Trpc) channels play important roles in the development of pathologic cardiac hypertrophy. Here, we demonstrated that Trpc3 mediates pathologic cardiac hypertrophy in neurohumoral elevation via direct regulation of CaV1.2 expressions. Elevated PE (phenylephrine) was maintained in mice by continuous infusion using an osmotic pump. Wild-type (WT) mice, but not Trpc3 −/− showed a sudden decrease in blood pressure (BP) or death following elevation of BP under conditions of elevated PE. Trpc3 −/− mesenteric artery showed decreased PE-stimulated vasoconstriction. Analysis of morphology, function, and pathologic marker expression revealed that PE elevation caused pathologic cardiac hypertrophy in WT mice, which was prevented by deletion of Trpc3. Interestingly, protection by Trpc3 deletion seemed to be a result of reduced cardiac CaV1.2 expressions. Basal and PE induced increased expression of protein and mRNA of CaV1.2 was decreased in Trpc3 −/− heart. Accordingly, altered expression of CaV1.2 was observed by knockdown or stimulation of Trpc3 in cardiomyocytes. These findings suggest that Trpc3 is a mediator of pathologic cardiac hypertrophy not only through mediating part of the Ca2+ influx, but also through control of CaV1.2 expressions.

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Abbreviations

[Ca2+]i :

Intracellular calcium concentration

Trpc:

Transient receptor potential canonical

BP:

Blood pressure

PE:

Phenylephrine

AngII:

AngiotensinII

Cn/Ca2+ :

Calmodulin-dependent protein phosphatase calcineurin

NFAT:

Nuclear factor of activated T cells

ANF:

Atrial natriuretic factor

BNP:

Brain natriuretic peptide

β-MHC:

Β-myosin heavy chain

OAG:

1-Oleoyl-2-acetyl-sn-glycerol

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Acknowledgments

We thank Jeungsik In in CPEC (Cardiovascular Product Evaluation Center) at Yonsei University Health System, Jangwoo Cho in SI healthcare and Heinmiller, Andrew in VisualSonics Inc. for helping echocardiogram measurements and analysis. This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (No. NRF-2011-0029459 for JY KIM, MSIP-2013R1A3A2042197 for MG LEE) and the Intramural Research Program of the NIH (Project Z01-ES101864 to LB).

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Authors and Affiliations

  1. Department of Pharmacology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea

    Jung Woo Han, Min Goo Lee & Joo Young Kim

  2. Department of Physiology and Brain Korea, 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, South Korea

    Young Ho Lee & Su-In Yoen

  3. Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, 27709, USA

    Joel Abramowitz & Lutz Birnbaumer

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  1. Jung Woo Han
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  2. Young Ho Lee
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Han, J.W., Lee, Y.H., Yoen, SI. et al. Resistance to pathologic cardiac hypertrophy and reduced expression of CaV1.2 in Trpc3-depleted mice. Mol Cell Biochem 421, 55–65 (2016). https://doi.org/10.1007/s11010-016-2784-0

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