title: Reduced L-arginine transport contributes to the pathogenesis of myocardial ischemia-reperfusion injury.
abstract: Myocardial injury due to ischemia-reperfusion (I-R) damage remains a major clinical challenge. Its pathogenesis is complex including endothelial dysfunction and heightened oxidative stress although the key driving mechanism remains uncertain. In this study we tested the hypothesis that the I-R process induces a state of insufficient L-arginine availability for NO biosynthesis, and that this is pivotal in the development of myocardial I-R damage. In neonatal rat ventricular cardiomyocytes (NVCM), hypoxia-reoxygenation significantly decreased L-arginine uptake and NO production (42 +/- 2% and 71 +/- 4%, respectively, both P < 0.01), maximal after 2 h reoxygenation. In parallel, mitochondrial membrane potential significantly decreased and ROS production increased (both P < 0.01). NVCMs infected with adenovirus expressing the L-arginine transporter, CAT1, and NVCMs supplemented with L-arginine both exhibited significant (all P < 0.05) improvements in NO generation and mitochondrial membrane potentials, with a concomitant significant fall in ROS production and lactate dehydrogenase release during hypoxia-reoxygenation. In contrast, L-arginine deprived NVCM had significantly worsened responses to hypoxia-reoxygenation. In isolated perfused mouse hearts, L-arginine infusion during reperfusion significantly improved left ventricular function after I-R. These improved contractile responses were not dependent on coronary flow but were associated with a significant decrease in nitrotyrosine formation and increases in phosphorylation of both Akt and troponin I. Collectively, these data strongly implicate reduced L-arginine availability as a key factor in the pathogenesis of I-R injury. Increasing L-arginine availability via increased CAT1 expression or by supplementation improves myocardial responses to I-R. Restoration of L-arginine availability may therefore be a valuable strategy to ameliorate I-R injury.
authors: Heart Failure Research Group, Baker IDI Heart & Diabetes Institute, Melbourne, Australia. kylie.venardos@bakeridi.edu.au
authors: Kylie M
authors: KM
authors: Venardos
authors: Amanda J
authors: AJ
authors: Zatta
authors: Tanneale
authors: T
authors: Marshall
authors: Rebecca
authors: R
authors: Ritchie
authors: David M
authors: DM
authors: Kaye
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D050916:TRPV Cation Channels; C120776:TRPV6 channel; D009569:Nitric Oxide; D001120:Arginine