TY - JOUR
T1 - Asymmetric Dimethyl l-Arginine (ADMA) is a critical regulator of myocardial reperfusion injury
AU - Stühlinger, Markus C.
AU - Conci, Elisabetta
AU - Haubner, Bernhard J.
AU - Stocker, Eva Maria
AU - Schwaighofer, Julia
AU - Cooke, John P.
AU - Tsao, Philip S.
AU - Pachinger, Otmar
AU - Metzler, Bernhard
N1 - Funding Information:
This study was supported by a grant from the “International Competitive Grants Program for Young Investigators” provided by the “GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease” (MCS), by a grant from the “Fonds zur Förderung von Wissenschaft und Forschung an den Universitätskliniken Innsbruck“ (MCS) and by a grant from the “Austrian Society of Cardiology” (BM). Dr. Cooke is an Established Investigator of the American Heart Association. The authors thank Dr. Masumi Kimoto from the Department of Nutritional Science (Faculty of Health and Welfare Science) at the Okayama Prefectural University (Japan) for providing monoclonal antibodies against human and rat DDAH-1.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/7/15
Y1 - 2007/7/15
N2 - Objective: Endothelial dysfunction by the loss of nitric oxide (NO) is a critical event during reperfusion of ischemic myocardium. Reduced NO availability signals important pathophysiological changes leading to myocardial reperfusion injury. We have recently shown that NO biosynthesis can be disturbed by the endogenous NO synthase (NOS) inhibitor ADMA and that these changes are mediated by an impairment of its metabolism by dimethylarginine dimethylaminohydrolase (DDAH). We therefore analyzed the role of ADMA and its metabolism in the setting of myocardial ischemia and reperfusion. Methods: C57-bl6 mice underwent myocardial ischemia for exactly 30 min followed by 2, 4, 8, 12, 24, and 72 h of reperfusion achieved by occlusion and re-opening of the left coronary artery. The reperfused left ventricle was subsequently homogenized for measurements of determinants of the NO synthase pathway. Furthermore, the effects and its mechanisms of ADMA on reperfusion injury were analyzed in a genetic mouse model. Results: A significant accumulation of ADMA was found in myocardial tissue when mice were subjected to 30 min of ischemia followed by reperfusion in our in vivo model. The maximum increase of tissue ADMA at 4 h of reperfusion coincided with reductions of NO tissue concentrations and DDAH activity; protein expression of NOS isoforms, however, was not changed. Furthermore, DDAH overexpression in a genetic mouse model as well as treatment with oral l-arginine markedly reduced reperfusion injury by 40-50% at 4 h of reperfusion. The effects of ADMA on reperfusion injury were shown to be mediated by reduced eNOS activity and phosphorylation, expression of adhesion molecules, and leukocyte activity. Conclusion: Accumulation of tissue ADMA by impairment of DDAH was found to be a significant determinant of reperfusion injury. Our results indicate that ADMA could be a potential new target for the treatment of myocardial ischemia/reperfusion injury.
AB - Objective: Endothelial dysfunction by the loss of nitric oxide (NO) is a critical event during reperfusion of ischemic myocardium. Reduced NO availability signals important pathophysiological changes leading to myocardial reperfusion injury. We have recently shown that NO biosynthesis can be disturbed by the endogenous NO synthase (NOS) inhibitor ADMA and that these changes are mediated by an impairment of its metabolism by dimethylarginine dimethylaminohydrolase (DDAH). We therefore analyzed the role of ADMA and its metabolism in the setting of myocardial ischemia and reperfusion. Methods: C57-bl6 mice underwent myocardial ischemia for exactly 30 min followed by 2, 4, 8, 12, 24, and 72 h of reperfusion achieved by occlusion and re-opening of the left coronary artery. The reperfused left ventricle was subsequently homogenized for measurements of determinants of the NO synthase pathway. Furthermore, the effects and its mechanisms of ADMA on reperfusion injury were analyzed in a genetic mouse model. Results: A significant accumulation of ADMA was found in myocardial tissue when mice were subjected to 30 min of ischemia followed by reperfusion in our in vivo model. The maximum increase of tissue ADMA at 4 h of reperfusion coincided with reductions of NO tissue concentrations and DDAH activity; protein expression of NOS isoforms, however, was not changed. Furthermore, DDAH overexpression in a genetic mouse model as well as treatment with oral l-arginine markedly reduced reperfusion injury by 40-50% at 4 h of reperfusion. The effects of ADMA on reperfusion injury were shown to be mediated by reduced eNOS activity and phosphorylation, expression of adhesion molecules, and leukocyte activity. Conclusion: Accumulation of tissue ADMA by impairment of DDAH was found to be a significant determinant of reperfusion injury. Our results indicate that ADMA could be a potential new target for the treatment of myocardial ischemia/reperfusion injury.
KW - Cell adhesion molecules
KW - Endothelium
KW - Infarction
KW - Ischemia
KW - Nitric oxide synthase
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U2 - 10.1016/j.cardiores.2007.04.030
DO - 10.1016/j.cardiores.2007.04.030
M3 - Article
C2 - 17559823
AN - SCOPUS:34250702757
SN - 0008-6363
VL - 75
SP - 417
EP - 425
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 2
ER -