Chen Kui, Mehta Jawahar L, Li Dayuan, Joseph Lija, Joseph Jacob
Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, USA.
Circ Res. 2004 Dec 10;95(12):1167-73. doi: 10.1161/01.RES.0000150369.68826.2f. Epub 2004 Nov 11.
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.
血管紧张素II（Ang II）是不良心脏重塑和纤维化的强效介质。然而，Ang II诱导心肌纤维化的机制仍有待阐明。我们推测，Ang II会改变转化生长因子β（TGF-β）受体的表达，特别是内皮糖蛋白的表达，从而调节心脏成纤维细胞（CF）的胶原代谢。使用成年Sprague Dawley大鼠的CF进行实验，以确定包括内皮糖蛋白在内的TGF-β1受体的表达，以及1型（AT1）和2型（AT2）血管紧张素II受体以及丝裂原活化蛋白激酶p42/44在此过程中的作用。还分析了内皮糖蛋白在调节Ang II对基质金属蛋白酶-1（MMP-1）和I型胶原表达的影响中的功能作用。在内皮静止的CF中持续鉴定到内皮糖蛋白基因和蛋白表达。Ang II以浓度和时间依赖性方式增加内皮糖蛋白mRNA和蛋白的表达，对I型和II型TGF-β受体的表达无影响。这种作用是由AT1受体介导的，因为AT1受体拮抗剂缬沙坦、坎地沙坦和氯沙坦可抑制Ang II诱导的内皮糖蛋白表达，而AT2受体拮抗剂PD123319则无作用。丝裂原活化蛋白激酶p42/44的抑制减弱了Ang II诱导的内皮糖蛋白表达。Ang II诱导的MMP-1蛋白表达降低和I型胶原蛋白表达增加均被特异性内皮糖蛋白抗体阻断。因此，我们的结果表明，Ang II通过AT1受体使CF中的内皮糖蛋白上调，并调节Ang II的促纤维化作用。这些发现为Ang II诱导的心脏重塑提供了新的见解。
