Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy.
Pathological cardiac hypertrophy (PCH) is associated with the development of arrhythmia and congestive heart failure. While calcium (Ca(2+)) is implicated in hypertrophic signaling pathways, the specific role of Ca(2+) influx through the L-type Ca(2+) channel (I(Ca-L)) has been controversial and is the topic of this study. To determine if and how sustained increases in I(Ca-L) induce PCH, transgenic mouse models with low (LE) and high (HE) expression levels of the β2a subunit of Ca(2+) channels (β2a) and in cultured adult feline (AF) and neonatal rat (NR) ventricular myocytes (VMs) infected with an adenovirus containing a β2a-GFP were used. In vivo, β2a 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 I(Ca-L), fractional shortening, peak Ca(2+) 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 β2a in cultured AFVMs increased I(Ca-L), cell volume, protein synthesis, NFAT, and HDAC translocations and in NRVMs increased surface area. These effects were abolished by the blockade of I(Ca-L), intracellular Ca(2+), calcineurin, CaMKII, and SERCA. In conclusion, increasing I(Ca-L) is sufficient to induce PCH through the calcineurin/NFAT and CaMKII/HDAC pathways. Both cytosolic and SR/ER-nuclear envelop Ca(2+) pools were shown to be involved.
Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA. xchen001@temple.edu
Xiongwen
X
Chen
Hiroyuki
H
Nakayama
Xiaoying
X
Zhang
Xiaojie
X
Ai
David M
DM
Harris
Mingxin
M
Tang
Hongyu
H
Zhang
Christopher
C
Szeto
Kathryn
K
Stockbower
Remus M
RM
Berretta
Andrea D
AD
Eckhart
Walter J
WJ
Koch
Jeffery D
JD
Molkentin
Steven R
SR
Houser
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology*; D002415:Cats; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D050778:NFATC Transcription Factors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium