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(Circulation Research. 2004;95:1167.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Transforming Growth Factor ß Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II

Kui Chen, Jawahar L. Mehta, Dayuan Li, Lija Joseph, Jacob Joseph

From the Departments of Medicine (K.C., J.L.M., D.L.), Physiology and Biophysics (J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock; and Departments of Medicine (J.J.) and Pathology (L.J.), VA Boston Healthcare System and Boston University School of Medicine, Boston, Mass.

Correspondence to Jacob Joseph, MD, Cardiology Section (111), VA Boston Healthcare System, 1400 VFW Pkwy, West Roxbury, MA 02132. E-mail jacob.joseph{at}med.va.gov

Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II–induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor ß (TGF-ß) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-ß₁ receptors including endoglin, and the role of Ang II type 1 (AT₁) and type 2 (AT₂) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-ß receptors I and II expression. This effect was AT₁ receptor mediated, because AT₁ receptor antagonists valsartan, candesartan, and losartan inhibited Ang II–induced endoglin expression, whereas the AT₂ receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II–induced endoglin expression. Ang II–induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT₁ receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II–induced cardiac remodeling.

Key Words: angiotensin II • collagen • endoglin • fibroblasts • remodeling

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