Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia.
Chronic systemic hypoxia (SH) enhances myocardial ischemic tolerance in mammals. We studied the delayed cardioprotection caused by acute SH and associated signaling mechanism. Conscious adult male mice were exposed to one or two cycles of hypoxia (H; 10% O(2)) or normoxia (21% O(2)) for various durations (30 min, 2 h, 4 h) followed by 24 h of reoxygenation. Hearts were isolated 24 h later and subjected to ischemia-reperfusion in a Langendorff model. Infarct size was reduced in mice pretreated with one (H4h) or two cycles (H4hx2) of 4 h SH compared with normoxia mice (P < 0.05), which was abolished by an inducible nitric oxide synthase (NOS2) inhibitor (S-methylisothiourea, 3 mg/kg) given before SH or ischemia. H4hx2 also failed to reduce infarct size in NOS2 knockout mice. Cyclooxygenase-2 (COX-2) inhibitor (NS-398, 10 mg/kg) did not block the protection given either before H4hx2 or ischemia. A two- to three fold increase in myocardial NOS2 expression was observed in H4h, H2hx2, and H4hx2 (P < 0.05), whereas endothelial NOS (NOS3) or COX-2 remained unchanged. We conclude that acute SH induces delayed cardioprotection, which is triggered and mediated by NOS2, but not by NOS3 or COX-2.
Xi
Lei
L
Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298-0281, USA.
Tekin
Demet
D
Gursoy
Erdal
E
Salloum
Fadi
F
Levasseur
Joseph E
JE
Kukreja
Rakesh C
RC
D000818:Animals; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006334:Heart Function Tests; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism; D015425:Myocardial Reperfusion; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases