Zhang Ping, Fassett John T, Zhu Guangshuo, Li Jingxin, Hu Xinli, Xu Xin, Chen Yingjie, Bache Robert J
1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
2 Department of Pharmacology and Toxicology, Karl Franzen University of Graz, Graz, Austria.
Vasc Med. 2017 Jun;22(3):179-188. doi: 10.1177/1358863X16681215. Epub 2017 Feb 1.
Pharmacologic inhibition of nitric oxide production inhibits growth of coronary collateral vessels. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme that degrades asymmetric dimethylarginine (ADMA), a potent inhibitor of nitric oxide synthase. Here we examined regulation of the ADMA-DDAH1 pathway in a canine model of recurrent myocardial ischemia during the time when coronary collateral growth is known to occur. Under basal conditions, DDAH1 expression was non-uniform across the left ventricular (LV) wall, with expression strongest in the subepicardium. In response to ischemia, DDAH1 expression was up-regulated in the midmyocardium of the ischemic zone, and this was associated with a significant reduction in myocardial interstitial fluid (MIF) ADMA. The decrease in MIF ADMA during ischemia was likely due to increased DDAH1 because myocardial protein arginine N-methyl transferase 1 (PRMT1) and the methylated arginine protein content (the source of ADMA) were unchanged or increased, respectively, at this time. The inflammatory mediators interleukin (IL-1β) and tumor necrosis factor (TNF-α) were also elevated in the midmyocardium where DDAH1 expression was increased. Both of these factors significantly up-regulated DDAH1 expression in cultured human coronary artery endothelial cells. Taken together, these results suggest that inflammatory factors expressed in response to myocardial ischemia contributed to up-regulation of DDAH1, which was responsible for the decrease in MIF ADMA.
一氧化氮生成的药理学抑制会抑制冠状动脉侧支血管的生长。二甲基精氨酸二甲胺水解酶1（DDAH1）是降解不对称二甲基精氨酸（ADMA）的主要酶，ADMA是一氧化氮合酶的强效抑制剂。在此，我们在已知会发生冠状动脉侧支生长的复发性心肌缺血犬模型中研究了ADMA-DDAH1途径的调节。在基础条件下，DDAH1表达在左心室（LV）壁上不均匀，在心外膜下表达最强。对缺血的反应是，缺血区心肌中层的DDAH1表达上调，这与心肌间质液（MIF）中ADMA的显著减少有关。缺血期间MIF中ADMA的减少可能是由于DDAH1增加，因为此时心肌蛋白精氨酸N-甲基转移酶1（PRMT1）和甲基化精氨酸蛋白含量（ADMA的来源）分别未变或增加。炎症介质白细胞介素（IL-1β）和肿瘤坏死因子（TNF-α）在DDAH1表达增加的心肌中层也升高。这两种因子均显著上调培养的人冠状动脉内皮细胞中的DDAH1表达。综上所述，这些结果表明，心肌缺血反应中表达的炎症因子促成了DDAH1的上调，而DDAH1上调导致了MIF中ADMA的减少。
