Published online before print January 22, 2004, doi: 10.1161/01.RES.0000118597.54416.00
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© 2004 American Heart Association, Inc.
UltraRapid Communication |
MCIP1 Overexpression Suppresses Left Ventricular Remodeling and Sustains Cardiac Function After Myocardial Infarction
From the Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands (E.v.R., P.A.D., L.J.D.W.), Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands; Departments of Cardiology (E.v.R., H.J.G.M.C., D.J.L.), Pathology (S.H.), and Physiology (M.v.B.), Cardiovascular Research Institute Maastricht, University Hospital Maastricht, the Netherlands; Heart Lung Center (P.A.D.), Utrecht, UMC, the Netherlands; Office of the Dean (R.S.W.), Duke University School of Medicine, Durham, NC; Department of Molecular Biology (E.N.O., R.B.-D.), and Internal Medicine (B.A.R.), University of Texas Southwestern Medical Center, Dallas, Tex.
Correspondence to Leon J. De Windt, PhD, Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Arts and Sciences, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. E-mail dewindt{at}niob.knaw.nl
Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation. MCIP1-TG mice and their wild-type (WT) littermates, were subjected to MI and analyzed 4 weeks later. At 4 weeks after MI, calcineurin was activated in the LV of WT mice, which was significantly reduced in MCIP1-TG mice. WT mice displayed a 78% increase in LV mass after MI, which was reduced by 38% in MCIP1-TG mice. Echocardiography indicated marked LV dilation and loss of systolic function in WT-MI mice, whereas TG-MI mice displayed a remarkable preservation of LV geometry and contractility, a pronounced reduction in myofiber hypertrophy, collagen deposition, and ß-MHC expression compared with WT-MI mice. Together, these results reveal a protective role for MCIP1 in the post-MI heart and suggest that calcineurin is a crucial regulator of postinfarction-induced pathological LV remodeling. The improvement in functional, structural, and molecular abnormalities in MCIP1-TG mice challenges the adaptive value of post-MI hypertrophy of the remote myocardium. The full text of this article is available online at http://circres.ahajournals.org.
Key Words: myocardial infarction • heart failure • calcineurin • signaling • hypertrophy
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