Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.
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 beta (TGF-beta) 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-beta1 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-beta 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.
Chen
Kui
K
Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, USA.
Mehta
Jawahar L
JL
Li
Dayuan
D
Joseph
Lija
L
Joseph
Jacob
J
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D000071063:Endoglin; D005347:Fibroblasts / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D024042:Collagen Type I; D000071063:Endoglin; C501740:Eng protein, rat; D005419:Flavonoids; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D018125:Receptors, Transforming Growth Factor beta; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D000068756:Valsartan; D020781:Matrix Metalloproteinase 1; D014633:Valine; D019808:Losartan; C081643:candesartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one