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Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling.

Abstract：

:Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs.

journal_name

J Mol Cell Cardiol

journal_title

Journal of molecular and cellular cardiology

authors

Gao H,Wang F,Wang W,Makarewich CA,Zhang H,Kubo H,Berretta RM,Barr LA,Molkentin JD,Houser SR

doi

10.1016/j.yjmcc.2012.08.005

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

657-67

issue

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(12)00294-5

journal_volume

pub_type

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Ca(2+) influx through L-type Ca(2+) channels and transient receptor potential channels activates pathological hypertrophy signaling.