5′‐AMP‐activated protein kinase activation prevents postischemic leukocyte‐endothelial cell adhesive interactions: Role of nitric oxide

Abstract

We have previously demonstrated that consuming ethanol (ethanol preconditioning) at low levels 24 hr prior to ischemia/reperfusion (I/R) prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism that is initiated by nitric oxide (NO) formed by endothelial NO synthase (eNOS). Recent work indicates that: 1) ethanol increases the activity of 5′-AMP-activated protein kinase (AMPK) and 2) AMPK phosphorylates eNOS at Ser1177, resulting in activation. In light of these observations, we postulated that AMPK activation may trigger the development of an anti-inflammatory phenotype similar to that induced by antecedent ethanol ingestion. C57BL/6J and eNOS−/− mice were treated with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) 24 hrs prior to I/R. I/R induced a marked increase in LEI relative to sham control mice. The postischemic increase in LEI was prevented by preconditioning with AICAR 24 hr prior to I/R. AICAR preconditioning appears to be mediated by NO, as it was ineffective at reducing LEI in the eNOS−/− mice or wild-type mice treated with the NOS inhibitor L-NAME. Our results indicate that AMPK agonists produce an anti-inflammatory phenotype in postcapillary venules by an NO-dependent mechanism. This work was supported by grants from the NIH (HL 54797 and DK 43785).