Transforming growth factor receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin ii.

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 and Jacob Joseph Circ. Res. 2004;95;1167-1173; originally published online Nov 11, 2004; DOI: 10.1161/01.RES.0000150369.68826.2f
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Molecular Medicine
Transforming Growth Factor 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
Abstract—Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of AngII–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-dependentmanner, 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 andincrease 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. (Circ Res. 2004;95:1167-1173.) Key Words: angiotensin II collagen endoglinfibroblasts remodeling

ctivation of the renin-angiotensin system (RAS) is a central mediator of progressive cardiac remodeling.1 Cardiac remodeling denotes alterations in the structural components of the myocardium involving both myocyte and nonmyocyte compartments, a process which underlies progressive heart failure.2 Angiotensin II (Ang II), the main effector hormone of the RAS, modulates cardiacremodeling by causing myocyte hypertrophy and myocardial fibrosis.3,4 Myocardial interstitial changes, characterized by increases in total fibrillar collagen (types I and III), changes in the ratio of types I/III collagen, and alterations in collagen cross-linking may adversely affect cardiac diastolic and systolic function.1,5,6 Various models of cardiac remodeling and failure have demonstrated...