Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

• Type of Material: Article
• Authors: Yevgeniya E. Koshman, Loyola University Chicago; Mark D. Sternlicht, FibroGen Inc; Taehoon Kim, Loyola University Chicago; Christopher P. O'Hara, Loyola University Chicago; Christopher Koczor, Emory University; William Lewis, Emory University; Todd W. Seeley, FibroGen Inc; Kenneth E. Lipson, FibroGen Inc; Allen M. Samarel, Loyola University Chicago
• Language: English
• Date: 2015-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.yjmcc.2015.11.003
• Title of Journal or Parent Work: Journal of Molecular and Cellular Cardiology
• ISSN: 0022-2828
• Volume: 89
• Issue: Pt B
• Start Page: 214
• End Page: 222
• Grant/Funding Information: This work was supported by the National Institutes of Health grant numbers P01 HL62426, 1F32 HL096143, and R01 DA-030996.
• Keywords: Science & Technology; FIBROSIS; Cardiovascular System & Cardiology; Gene array; Cardiac & Cardiovascular Systems; FACTOR EXPRESSION; Quantitative PCR; CHRONIC PRESSURE-OVERLOAD; Remodeling; Heart failure; Cell Biology; TROPONIN-I; MYOCARDIAL-INFARCTION; ALLOGRAFT-REJECTION; HYPERTROPHY; INDUCED HEART-FAILURE; GENE-EXPRESSION; Life Sciences & Biomedicine; BETA
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

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.