title: Connective tissue growth factor inhibition attenuates left ventricular remodeling and dysfunction in pressure overload-induced heart failure.
abstract: Connective tissue growth factor (CTGF) is involved in the pathogenesis of various fibrotic disorders. However, its role in the heart is not clear. To investigate the role of CTGF in regulating the development of cardiac fibrosis and heart failure, we subjected mice to thoracic aortic constriction (TAC) or angiotensin II infusion, and antagonized the function of CTGF with CTGF monoclonal antibody (mAb). After 8 weeks of TAC, mice treated with CTGF mAb had significantly better preserved left ventricular (LV) systolic function and reduced LV dilatation compared with mice treated with control immunoglobulin G. CTGF mAb-treated mice exhibited significantly smaller cardiomyocyte cross-sectional area and reduced expression of hypertrophic marker genes. CTGF mAb treatment reduced the TAC-induced production of collagen 1 but did not significantly attenuate TAC-induced accumulation of interstitial fibrosis. Analysis of genes regulating extracellular matrix proteolysis showed decreased expression of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 in mice treated with CTGF mAb. In contrast to TAC, antagonizing the function of CTGF had no effect on LV dysfunction or LV hypertrophy in mice subjected to 4-week angiotensin II infusion. Further analysis showed that angiotensin II-induced expression of hypertrophic marker genes or collagens was not affected by treatment with CTGF mAb. In conclusion, CTGF mAb protects from adverse LV remodeling and LV dysfunction in hearts subjected to pressure overload by TAC. Antagonizing the function of CTGF may offer protection from cardiac end-organ damage in patients with hypertension.
authors.affiliation: University of Oulu, Department of Pharmacology and Toxicology, P.O. Box 5000, FIN-90220 Oulu, Finland. Risto.Kerkela@oulu.fi.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szabó
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.forename: Tarja
authors.initials: T
authors.lastname: Alakoski
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.forename: Jarkko
authors.initials: J
authors.lastname: Piuhola
authors.forename: Laura
authors.initials: L
authors.lastname: Vainio
authors.forename: Kari I
authors.initials: KI
authors.lastname: Kivirikko
authors.forename: Olli
authors.initials: O
authors.lastname: Vuolteenaho
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Pierre
authors.initials: P
authors.lastname: Signore
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D003251:Constriction, Pathologic / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000150:complications* / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011312:Pressure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; C526318:CCN2 protein, mouse; D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2
keywords: connective tissue growth factor; fibrosis; hypertrophy, left ventricular; ventricular dysfunction, left; ventricular remodeling