Published online before print October 30, 2008, doi: 10.1161/CIRCRESAHA.108.180117
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Submitted on October 31, 2008
Revised on September 15, 2008
Accepted on October 16, 2008
B-Crystallin Suppresses Pressure Overload Cardiac Hypertrophy
Asangi R.K. Kumarapeli ;
From the Cardiovascular Research Institute and Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD. Present address for A.R.K.K.: Division of Cardiology/Cardiovascular Research, University of Pennsylvania School of Medicine, Philadelphia.
* To whom correspondence should be addressed. E-mail: xuejun.wang{at}usd.edu.
B-Crystallin (CryAB) is the most abundant small heat shock protein (HSP) constitutively expressed in cardiomyocytes. Gain- and loss-of-function studies demonstrated that CryAB can protect against myocardial ischemia/reperfusion injury. However, the role of CryAB or any HSPs in cardiac responses to mechanical overload is unknown. This study addresses this issue. Nontransgenic mice and mice with cardiomyocyte-restricted transgenic overexpression of CryAB or with germ-line ablation of the CryAB/HSPB2 genes were subjected to transverse aortic constriction or sham surgery. Two weeks later, cardiac responses were analyzed by fetal gene expression profiling, cardiac function analyses, and morphometry. Comparison among the 3 sham surgery groups reveals that CryAB overexpression is benign, whereas the knockout is detrimental to the heart as reflected by cardiac hypertrophy and malfunction at 10 weeks of age. Compared to nontransgenic mice, transgenic mouse hearts showed significantly reduced NFAT transactivation and attenuated cardiac hypertrophic responses to transverse aortic constriction but unchanged cardiac function, whereas NFAT transactivation was significantly increased in cardiac and skeletal muscle of the knockout mice at baseline, and they developed cardiac insufficiency at 2 weeks after transverse aortic constriction. CryAB overexpression in cultured neonatal rat cardiomyocytes significantly attenuated adrenergic stimulation-induced NFAT transactivation and hypertrophic growth. We conclude that CryAB suppresses cardiac hypertrophic responses likely through attenuating NFAT signaling and that CryAB and/or HSPB2 are essential for normal cardiac function.
Key words: heat shock proteins • hypertrophy • nuclear factors of activated T cells (NFAT) • myocyte-enriched calcineurin interacting protein-1 (MCIP1) • heart function • fetal genes
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