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

Abstract

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 β (TGF-β) 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-β 1 receptors including endoglin, and the role of Ang II type 1 (AT 1 ) and type 2 (AT 2 ) 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-β receptors I and II expression. This effect was AT 1 receptor mediated, because AT 1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II–induced endoglin expression, whereas the AT 2 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 AT 1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II–induced cardiac remodeling.