Journal
HYPERTENSION
Volume 55, Issue 5, Pages 1165-U153Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.109.147611
Keywords
hypertension; cardiac remodeling; TGF-beta; Smad3; angiotensin II
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Although Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-beta/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin 11 infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P<0.05), an increase in left ventricular mass (P<0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-beta 1, connective tissue growth factor, collagen 1/111, alpha-smooth muscle actin, interleukin 1 beta, tumor necrosis factor-alpha, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-celi infiltration in left, ventricular tissues (all P<0.01, respectively). Additional studies in vitro also revealed that angiotensin II induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor KB/p65 signaling pathways was a key mechanism by which Sinad3 KO mice were protected from angiotensin II mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease. (Hypertension. 2010;55:1165-1171.)
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