title: Arginase inhibition reduces infarct size via nitric oxide, protein kinase C epsilon and mitochondrial ATP-dependent K+ channels.
abstract: Reduced bioavailability of nitric oxide (NO) contributes to the development of myocardial ischemia-reperfusion (I/R) injury. Increased activity of arginase is a potential factor that reduces NO bioavailability by competing for the substrate L-arginine. The aim of the study was to test the hypothesis that inhibition of arginase after coronary artery occlusion protects from I/R injury and to explore possible mechanisms behind this effect. Male Sprague-Dawley rats subjected to 30 min of coronary artery ligation and 2h reperfusion were given i.v. before the reperfusion: 1) saline; 2) the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA); 3) nor-NOHA with the NO synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA); 4) nor-NOHA with the mitochondrial ATP-dependent K(+) (mitoKATP) channel blocker 5-hydroxydecanoic acid (5-HD); 5) nor-NOHA with the protein kinase C epsilon (PKCε) inhibitor ε-V1-2 or 6) ε-V1-2 alone. Infarct size in the control groups was 61±3% and it was reduced to 47±3% (P<0.01) by nor-NOHA. The cardioprotective effect was blocked by the NOS inhibitor L-NMMA. PKCε expression was reduced by I/R and this reduction was attenuated by nor-NOHA. Furthermore, the PKCε inhibitor ε-V1-2 abolished the protective effect of nor-NOHA (infarct size 69±6%). In addition, the cardioprotective effect of nor-NOHA was also abolished following blockade of the mitoKATP channel (infarct size 62±1%). Inhibition of arginase before reperfusion protects the heart from I/R injury via a NOS-dependent pathway, increased expression of PKCε and activation of mitoKATP channels.
authors.affiliation: Department of Medicine, Division of Cardiology, Karolinska Institutet, Karolinska, University Hospital, S-171 76 Stockholm, Sweden. yahor.tratsiakovich@ki.se
authors.forename: Yahor
authors.initials: Y
authors.lastname: Tratsiakovich
authors.forename: Adrian Thomas
authors.initials: AT
authors.lastname: Gonon
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: Jiangning
authors.initials: J
authors.lastname: Yang
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.forename: Per-Ove
authors.initials: PO
authors.lastname: Sjöquist
authors.forename: John
authors.initials: J
authors.lastname: Pernow
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D015221:Potassium Channels / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control
chemical_list: D004791:Enzyme Inhibitors; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; D051744:Protein Kinase C-epsilon; D001119:Arginase