Published online before print November 11, 2004, doi: 10.1161/01.RES.0000150369.68826.2f
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Submitted on August 6, 2004
Revised on October 21, 2004
Accepted on November 1, 2004
Transforming Growth Factor 
Receptor Endoglin Is Expressed in Cardiac Fibroblasts and Modulates Profibrogenic Actions of Angiotensin II
Kui Chen ;
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.
* To whom correspondence should be addressed. 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 
(TGF-) 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-1 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- 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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