Muscle ring finger 1 mediates cardiac atrophy in vivo

• Published in: American journal of physiology. Heart and circulatory physiology 2009-04, Vol.296 (4), p.H997-H1006
• Main Authors: Willis, Monte S, Rojas, Mauricio, Li, Luge, Selzman, Craig H, Tang, Ru-Hang, Stansfield, William E, Rodriguez, Jessica E, Glass, David J, Patterson, Cam
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Atrophy - chemically induced; Atrophy - metabolism; Atrophy - pathology; Dexamethasone - adverse effects; Disease Models, Animal; Gene expression; Heart; Heart Diseases - chemically induced; Heart Diseases - metabolism; Heart Diseases - pathology; Heart failure; Heart-Assist Devices; Mice; Mice, Knockout; Muscle Proteins - metabolism; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - pathology; Natriuretic Peptide, Brain - metabolism; Regression analysis; Rodents; Studies; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - metabolism; Vasoconstriction; Ventricular Myosins - metabolism
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00660.2008

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