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Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats

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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)-β1 expression, which in turn triggers a series of fibrogenic responses. Sprague–Dawley rats were treated with angiotensin (Ang)II (9 μg/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-β1, 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 (gp91phox subunit) expression. Co-treatment with antioxidants led to: (1) markedly decreased cardiac gp91phox; (2) significantly attenuated gene expression of TGF-β1, 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-β1 expression, which subsequently enhances cardiac collagen synthesis and suppresses collagen degradation in hypertensive rats.

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Acknowledgments

This work was supported by the National Heart, Lung, and Blood Institute (RO1-HL077668 to Yao Sun).

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Correspondence to Yao Sun.

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Zhao, W., Zhao, T., Chen, Y. et al. Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem 317, 43–50 (2008). https://doi.org/10.1007/s11010-008-9803-8

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