title: Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Naoki
authors.initials: N
authors.lastname: Sugano
authors.forename: Masumi
authors.initials: M
authors.lastname: Kimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000581:Amidohydrolases / Q000096:biosynthesis* / Q000235:genetics; D017311:Amlodipine / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D052279:Creatine Kinase, MB Form; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology; D005355:Fibrosis / Q000201:enzymology / Q000473:pathology; D006331:Heart Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D017540:Tunica Media / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014665:Vasodilator Agents; D000804:Angiotensin II; D017311:Amlodipine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D048051:p38 Mitogen-Activated Protein Kinases; D052279:Creatine Kinase, MB Form; D007703:Peptidyl-Dipeptidase A; D000581:Amidohydrolases; C059999:dimethylargininase; C093642:SB 203580