Journal
CIRCULATION
Volume 116, Issue 5, Pages 535-544Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.107.689471
Keywords
ischemia; myocardial infarction; occlusion; stress
Funding
- NHLBI NIH HHS [R37 HL055757, R01 HL055757, P10 HL-78825, HL-55757, R01 HL-65660, R01 HL065660, R01 HL068088, R01 HL068088-05, R01 HL070897, HL-70897, HL-68088, R01 HL076794, HL-76794, P01 HL078825] Funding Source: Medline
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Background - The role of endothelial nitric oxide synthase (eNOS) in ischemic preconditioning ( PC) and cardioprotection is poorly understood. We addressed this issue using a genetic, rather than pharmacological, approach. Methods and Results - In the nonpreconditioned state, eNOS(-/-) mice exhibited infarct sizes similar to those of wild-type mice. A sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles ( ischemic PC) induced late PC in wild-type mice; genetic deletion of eNOS abrogated the cardioprotection induced by late PC. In wild-type mice, ischemic PC induced membranous translocation of protein kinase C (PKC)epsilon and an increase in pSer-MEK-1/2 and pTyr-p44/42 mitogen-activated protein kinase, nuclear pSer-signal transducers and activators of transcription (STAT) 1 and pSer-STAT3, and nuclear STAT1/3 DNA binding activity, followed by upregulation of cyclooxygenase-2 protein and activity 24 hours later. All of these changes were abrogated in eNOS(-/-) mice. The NO donor diethylenetriamine/NO recapitulated the effects of ischemic PC. Conclusions - In contrast to previous reports, we found that basal eNOS activity does not modulate infarct size in the nonpreconditioned state. However, eNOS is obligatorily required for the development of the cardioprotective effects of late PC and acts as the trigger of this process by activating the PKC epsilon-MEK-1/2-p44/42 mitogen-activated protein kinase pathway, leading to Ser-727 phosphorylation of STAT1 and STAT3 and consequent upregulation of STAT-dependent genes such as cyclooxygenase-2. The effects of eNOS-derived NO are reproduced by exogenous NO ( NO donors), implying that nitrates can upregulate cardiac cyclooxygenase-2.
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