CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload. (November 2015)

• Record Type: Journal Article
• Authors: Fontes, Magda S.C.; Kessler, Elise L.; van Stuijvenberg, Leonie; Brans, Maike A.; Falke, Lucas L.; Kok, Bart; Leask, Andrew; van Rijen, Harold V.M.; Vos, Marc A.; Goldschmeding, Roel; van Veen, Toon A.B.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 88(2015:Nov.)
• Page Start: 82
• Page End: 90
• Publication Date: 2015-11
• Subjects: CTGF -- Fibrosis -- Hypertrophy -- Arrhythmias; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2015.09.015
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. However, recent studies have questioned the role of CTGF as a pro-fibrotic factor. Therefore, we aimed to investigate the effect of CTGF on cardiac fibrosis, and on functional, structural, and electrophysiological parameters in a mouse model of CTGF knockout (KO) and chronic pressure overload. Methods and results: A new mouse model of global conditional CTGF KO induced by tamoxifen-driven deletion of CTGF, was subjected to 16 weeks of chronic pressure overload via transverse aortic constriction (TAC, control was sham surgery). CTGF KO TAC mice presented with hypertrophic hearts, and echocardiography revealed a decrease in contractility on a similar level as control TAC mice. Ex vivo epicardial mapping showed a low incidence of pacing-induced ventricular arrhythmias (2/12 in control TAC vs. 0/10 in CTGF KO TAC, n.s. ) and a tendency towards recovery of the longitudinal conduction velocity of CTGF KO TAC hearts. Picrosirius Red staining on these hearts unveiled increased fibrosis at a similar level as control TAC hearts. Furthermore, genes related to fibrogenesis were also similarly upregulated in both TAC groups. Histological analysis revealed an increase in fibronectin and vimentin protein expression, a significant reduction in connexin43 (Cx43) protein expression, and no difference in NaV 1.5 expression of CTGF KO ventricles as compared with sham treated animals. Conclusion: Conditional CTGF inhibition failed to prevent TAC-induced cardiac fibrosis and hypertrophy. Additionally, no large differences were found in other parameters between CTGF KO and control TAC mice. With no profound effect of CTGF on fibrosis formation, other factors or pathways are likely responsible for fibrosis development. Highlights: Conditional CTGF knockout failed to prevent TAC-induced fibrosis and hypertrophy. CTGF KO did not affect contractility, Cx43 expression, or other parameters upon TAC. CTGF is not essential for fibrosis formation in the heart.