title: Repetitive ischemia increases myocardial dimethylarginine dimethylaminohydrolase 1 expression.
abstract: 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.
authors.affiliation: 1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: 2 Department of Pharmacology and Toxicology, Karl Franzen University of Graz, Graz, Austria.
authors.forename: John T
authors.initials: JT
authors.lastname: Fassett
authors.affiliation: 1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.affiliation: 3 Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
authors.affiliation: 4 Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.affiliation: 1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1 Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003097:Collateral Circulation; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D042783:Endothelial Cells / Q000201:enzymology; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018919:Neovascularization, Physiologic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C018524:N,N-dimethylarginine; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D011484:Protein-Arginine N-Methyltransferases; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: IL-1β; TNF-α; asymmetric dimethylarginine (ADMA); nitric oxide synthase; protein arginine methyl transferase