Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling
Androgen-Androgen Receptor System Protects against Angiotensin II-Induced Vascular Remodeling
复制标题
DOI：
10.1210/en.2008-1254
复制
发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Matsumoto, Toshio
中科院分区：
文献类型：
--
作者：
Ikeda, Yasumasa;Aihara, Ken-ichi;Matsumoto, Toshio
男性更年期与心血管疾病有关。虽然我们以前曾报道雄激素-雄激素受体（AR）系统在心脏生长和重塑中起重要作用，但该系统在血管重塑中的作用仍不清楚。为了阐明这一作用，将25周龄雄性AR敲除（ARKO）小鼠和同窝雄性野生型（WT）小鼠分为两组，分别给予和不给予血管紧张素II（Ang II）（2.0 mg/kg.d）14 d。无Ang II组之间冠状动脉和胸主动脉无形态学差异。血管紧张素II刺激显着增加中膜厚度和血管周围纤维化的ARKO小鼠，增强TGF-β 1，胶原蛋白I型和胶原蛋白III型基因表达的主动脉。与WT小鼠相比，ARKO小鼠中Ang II刺激还显著增加了超氧化物的产生、脂质过氧化和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶组分的基因表达。此外，与Ang II处理的WT小鼠相比，Ang II处理的ARKO小鼠中c-Jun N-末端激酶（JNK）和磷酸化（Smad 2/3）的磷酸化显著增强。值得注意的是，每日尿一氧化氮（NO）代谢物排泄作为NO生物利用度，主动脉内皮NO合酶的表达和磷酸化，Akt磷酸化的标志物显着减少ARKO小鼠与WT小鼠相比，无论血管紧张素II刺激。总之，雄激素-AR系统是通过Akt-内皮NO合酶系统激活来保护NO生物利用度所必需的，并且通过调节氧化应激、c-Jun N-末端激酶（JNK）信号传导和TGF-β-磷酸化Smad通路来对Ang II诱导的血管重塑发挥保护作用。（内分泌学150：2857-2864，2009）
Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system's involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg.d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-beta 1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-beta-phosphorylated Smad pathway. (Endocrinology 150: 2857-2864, 2009)