Hasegawa Kazuhiro, Wakino Shu, Tatematsu Satoru, Yoshioka Kyoko, Homma Koichiro, Sugano Naoki, Kimoto Masumi, Hayashi Koichi, Itoh Hiroshi
Department of Internal Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
Circ Res. 2007 Jul 20;101(2):e2-10. doi: 10.1161/CIRCRESAHA.107.156901. Epub 2007 Jun 29.
Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated transgenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP kinase inhibition by SB203580. In wild-type mice, long-term treatment with angiotensin II increased plasma ADMA and cardiac oxidative stress and caused similar vascular injury. In transgenic mice, these changes were attenuated. The present study suggests that DDAH2/ADMA regulates cardiac NO levels but has modest effect on SBP in normal conditions. Under the circumstances where plasma ADMA are elevated, including angiotensin II-activated conditions, ADMA serves to contribute to the development of vascular injury and increased cardiac oxidative stress, and the overexpression of DDAH2 attenuates these abnormalities. Collectively, the DDAH2/ADMA pathway can be a novel therapeutic target for vasculopathy in the ADMA or angiotensin II-induced pathophysiological conditions.
二甲基精氨酸二甲胺水解酶（DDAH）可降解内源性一氧化氮（NO）合酶抑制剂不对称二甲基精氨酸（ADMA），它有两种亚型，即DDAH1和DDAH2。为了研究DDAH2在体内的作用，我们构建了过表达DDAH2的转基因小鼠。与野生型小鼠相比，转基因小鼠的血浆ADMA水平降低，心脏NO水平升高，但全身血压（SBP）没有变化。当向野生型小鼠输注ADMA 4周时，ADMA使SBP升高，并导致冠状动脉微血管明显的中层增厚和血管周围纤维化，同时伴有ACE蛋白上调和心脏氧化应激。氨氯地平治疗可降低SBP，但未能改善ADMA诱导的组织学变化。相比之下，在转基因小鼠中，随着血浆ADMA的降低，这些变化消失了。在冠状动脉内皮细胞中，ADMA激活p38丝裂原活化蛋白激酶，而SB203580抑制p38丝裂原活化蛋白激酶可抑制ADMA诱导的ACE上调。在野生型小鼠中，长期用血管紧张素II治疗会增加血浆ADMA和心脏氧化应激，并导致类似的血管损伤。在转基因小鼠中，这些变化减弱。本研究表明，在正常情况下，DDAH2/ADMA调节心脏NO水平，但对SBP影响不大。在血浆ADMA升高的情况下，包括血管紧张素II激活的情况，ADMA会导致血管损伤的发展和心脏氧化应激增加，而DDAH2的过表达可减轻这些异常。总的来说，在ADMA或血管紧张素II诱导的病理生理条件下，DDAH2/ADMA途径可能是血管病变的一个新的治疗靶点。
