Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 317, Issue 1-2, Pages 43-50Publisher
SPRINGER
DOI: 10.1007/s11010-008-9803-8
Keywords
hypertension; angiotensin II; oxidative stress; cardiac fibrosis
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Funding
- National Heart, Lung, and Blood Institute [RO1-HL077668]
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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)-beta 1 expression, which in turn triggers a series of fibrogenic responses. Sprague-Dawley rats were treated with angiotensin (Ang)II (9 mu g/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-beta 1, 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-beta 1, 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-beta 1 expression, which subsequently enhances cardiac collagen synthesis and suppresses collagen degradation in hypertensive rats.
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