title: Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy.
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.
authors.affiliation: The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States.
authors.forename: Yevgeniya E
authors.initials: YE
authors.lastname: Koshman
authors.affiliation: FibroGen, Inc., San Francisco, CA 94158, United States.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Sternlicht
authors.affiliation: The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States.
authors.forename: Taehoon
authors.initials: T
authors.lastname: Kim
authors.affiliation: The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Hara
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Koczor
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States.
authors.forename: William
authors.initials: W
authors.lastname: Lewis
authors.affiliation: FibroGen, Inc., San Francisco, CA 94158, United States.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Seeley
authors.affiliation: FibroGen, Inc., San Francisco, CA 94158, United States.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.affiliation: The Cardiovascular Research Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, United States. Electronic address: asamare@luc.edu.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Samarel
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D055513:Connective Tissue Growth Factor; D003094:Collagen; D051744:Protein Kinase C-epsilon
keywords: Gene array; Heart failure; Quantitative PCR; Remodeling