Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 50, Issue 3, Pages 460-470Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2010.11.012
Keywords
L-type calcium channel (or Cav1.2); beta(2a) Subunit; Ventricular myocyte; Hypertrophy; Transgenic mouse
Categories
Funding
- NIH [HL089312, HL088243]
- HHMI
- American Heart Association [AHA0730347N]
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Pathological cardiac hypertrophy (PCH) is associated with the development of arrhythmia and congestive heart failure. While calcium (Ca2+) is implicated in hypertrophic signaling pathways, the specific role of Ca2+ influx through the L-type Ca2+ channel (ICa-L) has been controversial and is the topic of this study. To determine if and how sustained increases in ICa-L induce PCH, transgenic mouse models with low (LE) and high (HE) expression levels of the beta 2a subunit of Ca2+ channels (beta 2a) and in cultured adult feline (AF) and neonatal rat (NR) ventricular myocytes (VMS) infected with an adenovirus containing a beta 2a-GFP were used. In vivo, beta 2a LE and HE mice had increased heart weight to body weight ratio, posterior wall and interventricular septal thickness, tissue fibrosis, myocyte volume, and cross-sectional area and the expression of PCH markers in a time- and dose-dependent manner. PCH was associated with a hypercontractile phenotype including enhanced ICa-L, fractional shortening, peak Ca2+ transient, at the myocyte level, greater ejection fraction, and fractional shortening at the organ level. In addition, LE mice had an exaggerated hypertrophic response to transverse aortic constriction. In vitro overexpression of beta 2a in cultured AFVMs increased ICa-L, cell volume, protein synthesis, NFAT, and HDAC translocations and in NRVMs increased surface area. These effects were abolished by the blockade of ICa-L, intracellular Ca2+, calcineurin, CaMKII, and SERCA. In conclusion, increasing ICa-L is sufficient to induce PCH through the calcineurin/NFAT and CaMKII/HDAC pathways. Both cytosolic and SR/ER-nuclear envelop Ca2+ pools were shown to be involved. (C) 2010 Elsevier Ltd. All rights reserved.
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