Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science. 2011 Apr 15;332(6027):361-5. doi: 10.1126/science.1192152.
Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.
血管紧张素 II（AngII）介导主动脉瘤的进展，但它的 1 型（AT1）和 2 型（AT2）受体的相对贡献尚不清楚。我们表明，在马凡综合征（MFS）小鼠模型中，AT2 表达的缺失加速了主动脉的异常生长和破裂。选择性 AT1 受体阻滞剂（ARB）氯沙坦阻断了小鼠的动脉瘤进展；完整的 AT2 信号通路需要完整的保护。血管紧张素转换酶抑制剂（ACEi）依那普利限制了两种受体的信号传递，效果较差。这两种药物都能减弱主动脉中典型的转化生长因子-β（TGFβ）信号，但氯沙坦通过允许 AT2 持续信号传递，独特地抑制了 TGFβ 介导的细胞外信号调节激酶（ERK）的激活。这些数据强调了 AT2 信号的保护性质，并可能为 MFS 和相关疾病的治疗选择提供信息。
