title: Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats.
abstract: Cardiac fibrosis represented as perivascular/interstial fibrosis occurs in patients with hypertension. Oxidative stress has been demonstrated to contribute to such structural remodeling. The underlying mechanisms, however, remain to be elucidated. Herein, we tested the hypothesis that oxidative stress mediates cardiac fibrogenesis by stimulating transforming growth factor (TGF)-beta1 expression, which in turn triggers a series of fibrogenic responses. Sprague-Dawley rats were treated with angiotensin (Ang)II (9 microg/h s) for 4 weeks with/without co-treatment of combined antioxidants, apocynin, and tempol (120 mg/kg/day each, oral). Untreated rats served as controls. Appearance of cardiac oxidative stress and its potential effect on the expression of TGF-beta1, population of myofibroblasts, collagen synthesis/degradation, and fibrosis in hearts were examined. Chronic AngII infusion elevated systemic blood pressure (210 +/- 5 mmHg). Extensive perivascular and interstitial fibrosis was found in both ventricles, which were co-localized with oxidative stress represented as upregulated NADPH oxidase (gp91(phox) subunit) expression. Co-treatment with antioxidants led to: (1) markedly decreased cardiac gp91(phox); (2) significantly attenuated gene expression of TGF-beta1, type-I collagen, and tissue inhibitors of matrix metalloproteinase (TIMP)-I/II in the heart; (3) largely reduced population of myofibroblasts at sites of fibrosis; (4) significantly reduced cardiac collagen volume; (5) and partially suppressed blood pressure (190 +/- 4 mmHg). Thus, cardiac oxidative stress promotes the development of cardiac fibrosis by upregulating TGF-beta1 expression, which subsequently enhances cardiac collagen synthesis and suppresses collagen degradation in hypertensive rats.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue Rm B310, Memphis, TN, 38163, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Tieqiang
authors.initials: T
authors.lastname: Zhao
authors.forename: Yuanjian
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013599:Systole / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D024042:Collagen Type I; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases