Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

Oakley R.H.; Ren R.; Cruz-Topete D.Bird G.S.Myers P.H.Boyle M.C.Schneider M.D.Willis M.S.Cidlowski J.A.

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Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

机译：Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

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Heart failure is a leading cause of death in humans, and stress is increasingly associated with adverse cardiac outcomes. Glucocorticoids are primary stress hormones, but their direct role in cardiovascular health and disease is poorly understood. To determine the in vivo function of glucocorticoid signaling in the heart, we generated mice with cardiomyocyte-specific deletion of the glucocorticoid receptor (GR). These mice are born at the expected Mendelian ratio, but die prematurely from spontaneous cardiovascular disease. By 3 mo of age, mice deficient in cardiomyocyte GR display a marked reduction in left ventricular systolic function, as evidenced by decreases in ejection fraction and fractional shortening. Heart weight and left ventricular mass are elevated, and histology revealed cardiac hypertrophy without fibrosis. Removal of endogenous glucocorticoids and mineralocorticoids neither augmented nor lessened the hypertrophic response. Global gene expression analysis of knockout hearts before pathology onset revealed aberrant regulation of a large cohort of genes associated with cardiovascular disease as well as unique disease genes associated with inflammatory processes. Genes important for maintaining cardiac contractility, repressing cardiac hypertrophy, promoting cardiomyocyte survival, and inhibiting inflammation had decreased expression in the GR-deficient hearts. These findings demonstrate that a deficiency in cardiomyocyte glucocorticoid signaling leads to spontaneous cardiac hypertrophy, heart failure, and death, revealing an obligate role for GR in maintaining normal cardiovascular function. Moreover, our findings suggest that selective activation of cardiomyocyte GR may represent an approach for the prevention of heart disease.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第42期|17035-17040|共6页
作者
Oakley R.H.; Ren R.; Cruz-Topete D.Bird G.S.Myers P.H.Boyle M.C.Schneider M.D.Willis M.S.Cidlowski J.A.;
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作者单位

Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Department of Health and Human Services, Research Triangle Park, NC 27709, United States;

Comparative Medicine Branch, National Institute of Environmental Health Sciences, Department of Health and Human Services, Research Triangle Park, NC 27709, United States;

Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Department of Health and Human Services, Research Triangle Park, NC 27709, United StatesNational Heart and Lung Institute, Imperial College London, London SW7 2AZ, United KingdomDepartment of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Essential; role; stress;

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

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