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Muscle ring finger 1 mediates cardiac atrophy in vivo

¹Carolina Cardiovascular Biology Center, ²Department of Pathology and Laboratory Medicine, and ³Department of Surgery, University of North Carolina, Chapel Hill, North Carolina; ⁴Novartis Institutes for Biomedical Research Incorporated, Cambridge, Massachusetts; ⁵Departments of Medicine, Pharmacology, and Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina; ⁶Division of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah

Submitted 23 June 2008 ; accepted in final form 21 January 2009

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1^–/– mice decreased 70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by β-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1^–/– and wild-type hearts after TAC release. In the second model, MuRF1^–/– mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.

ubiquitin ligase; cardiac hypertrophy; cardiac atrophy; left ventricular assist device

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