Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy |
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| Affiliation: | 1. The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States;2. FibroGen, Inc., San Francisco, CA 94158, United States;3. Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States;1. The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States;2. Division of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;1. Department of Cellular and Molecular Medicine, University of Arizona, 1656 East Mabel Street, Tucson, AZ 85724, USA;2. Department of Anaesthesiology and Operative Intensive Care, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany;1. Vanderbilt Center for Arrhythmia Research and Therapeutics, Vanderbilt University School of Medicine, Nashville, TN, USA;2. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA;3. Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA;1. Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA;2. Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA, USA;3. Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA;4. Cardiovascular Division, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA, USA |
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| Abstract: | Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective tissue growth factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic functions in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling was elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted. |
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