Ca2+ influx through L-type Ca2+ channels and transient receptor potential channels activates pathological hypertrophy signaling

被引:76
作者
Gao, Hui [1 ,2 ]
Wang, Fang [1 ,2 ]
Wang, Wei [1 ,2 ]
Makarewich, Catherine A. [1 ,2 ]
Zhang, Hongyu [1 ,2 ]
Kubo, Hajime [1 ,2 ]
Berretta, Remus M. [1 ,2 ]
Barr, Larry A. [1 ,2 ]
Molkentin, Jeffery D. [3 ]
Houser, Steven R. [1 ,2 ]
机构
[1] Temple Univ, Sch Med, Cardiovasc Res Ctr, Philadelphia, PA 19140 USA
[2] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19140 USA
[3] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA
关键词
L-type calcium channel; Hypertrophy; Nuclear factor of activated T cells; Ventricular myocyte; Transient receptor potential channel; INDUCED CARDIAC-HYPERTROPHY; RAT VENTRICULAR MYOCYTES; CALCIUM-CHANNEL; ANGIOTENSIN-II; TRPC CHANNELS; HEART; GENE; CONTRACTION; ANTAGONIST; EXPRESSION;
D O I
10.1016/j.yjmcc.2012.08.005
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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 [Ca2+]. These diseases induce cardiac hypertrophy and increases in [Ca2+] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca2+] is not known and is the topic of this study. The role of Ca2+ influx through L-type Ca2+ channels (LTCC), T-type Ca2+ 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 Ca2+ or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca2+-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TFCC antagonist) were less effective. The relative potency of these antagonists against Ca2+ induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca2+ 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 Ca2+ influx through LTCCs is the primary source of Ca2+ to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca2+ entry via LTCCs. (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码:657 / 667
页数:11
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