Hypertension & Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA.
Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1328-38. doi: 10.1152/ajpheart.00538.2010. Epub 2010 Sep 10.
Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling-positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-β(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis.
血管紧张素 II（ANG II）可导致高血压、心肌肥厚、纤维化和功能障碍；然而，在体内将 ANG II 的心脏效应与其血液动力学作用分开是很困难的。为了克服这些限制，我们使用了一种转基因小鼠，其心肌细胞中表达一种转基因融合蛋白，该蛋白可从心肌细胞中释放 ANG II（Tg-ANG II），并用脱氧皮质酮醋酸盐（DOCA-盐）处理它们以抑制其全身肾素-血管紧张素系统。使用这种独特的模型，我们检验了这样一个假设，即心脏 ANG II 通过血管紧张素 1 型受体（AT(1)R）发挥作用，增加炎症、氧化应激和细胞凋亡，从而加速心肌肥厚和纤维化。雄性 Tg-ANG II 小鼠及其非转基因同窝仔（n-Tg）被单侧肾切除，并分为以下三组：1）载体处理的正常血压对照组；2）DOCA-盐；3）DOCA-盐+缬沙坦（AT(1)R 阻滞剂）。在基础条件下，两种品系的收缩压（SBP）和心脏表型相似。在 DOCA-盐性高血压中，n-Tg 和 Tg-ANG II 的 SBP 升高相似，两种品系的心脏功能没有差异；然而，Tg-ANG II 有 1）更大的心室肥厚以及间质和血管周围纤维化；2）更多的脱氧核苷酸转移酶介导的 dUTP 缺口末端标记阳性细胞和浸润的巨噬细胞；3）NADPH 氧化酶 2 和转化生长因子-β(1)的蛋白表达增加；以及 4）磷脂酰肌醇 3-激酶（PI 3-kinase）和蛋白激酶 B（Akt）磷酸化的下调。缬沙坦部分逆转了 Tg-ANG II 中的这些作用，但在 n-Tg 中没有。我们得出结论，当血流动力学负荷条件保持不变时，心脏 ANG II 不会改变心脏大小或心脏功能。然而，在高血压动物中，心脏 ANG II 通过 AT(1)R 作用，增强炎症、氧化应激和细胞死亡（很可能通过下调 PI 3-kinase 和 Akt），导致心肌肥厚和纤维化。
