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Am J Physiol Heart Circ Physiol 292: H326-H332, 2007. First published August 25, 2006; doi:10.1152/ajpheart.00744.2006
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5'-AMP-activated protein kinase activation prevents postischemic leukocyte-endothelial cell adhesive interactions

Department of Medical Pharmacology and Physiology, and the Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri

Submitted 11 July 2006 ; accepted in final form 24 August 2006

Preconditioning (PC) with nitric oxide (NO) donors or agents that increase endothelial NO synthase (eNOS) activity 24 h before ischemia-reperfusion (I/R) prevents postischemic leukocyte rolling (LR) and stationary leukocyte adhesion (LA). Since 5'-AMP-activated protein kinase (AMPK) phosphorylates eNOS at Ser1177, resulting in activation, we postulated that AMPK activation may trigger the development of a preconditioned anti-inflammatory phenotype similar to that induced by NO donors. Wild-type (WT) C57BL/6J and eNOS^–/– mice were treated with the AMPK agonist 5-aminoimidazole-4-carboxamide 1--D-furanoside (AICAR) 30 min (early AICAR PC) or 24 h (late AICAR PC) before I/R; LR and LA were quantified in single postcapillary venules in the jejunum using intravital microscopy. I/R induced comparable marked increases in LR and LA in WT and eNOS^–/– mice relative to sham-operated (no ischemia) animals. Late AICAR PC prevented postischemic LR and LA, whereas early AICAR PC prevented LA in WT mice. Late AICAR PC was ineffective in preventing I/R-induced LR but not LA in the eNOS^–/– mice, and the same pattern was seen in WT animals treated with the NOS inhibitor N-nitro-L-arginine. Early AICAR PC remained effective in preventing LA in eNOS^–/– mice. Our results indicate that both early and late PC with an AMPK agonist produces an anti-inflammatory phenotype in postcapillary venules. Since the protection afforded by late AICAR PC on postischemic LR was prevented by NOS inhibition in WT mice and absent in eNOS-deficient mice, it appears that eNOS triggers this protective effect. In stark contrast, antecedent AMPK activation prevented I/R-induced LA by an eNOS-independent mechanism.

ischemia; reperfusion; leukocyte rolling and adhesion; endothelial nitric oxide synthase-deficient mice

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