Isoform-selective 5'-AMP-activated protein kinase-dependent preconditioning mechanisms to prevent postischemic leukocyte-endothelial cell adhesive interactions.
We previously demonstrated that preconditioning induced by ethanol consumption at low levels [ethanol preconditioning (EPC)] or with 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR-PC) 24 h before ischemia-reperfusion prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism that is initiated by nitric oxide formed by endothelial nitric oxide synthase. Recent work indicates that 1) ethanol increases the activity of AMP-activated protein kinase (AMPK) and 2) AMPK phosphorylates endothelial nitric oxide synthase at the same activation site seen following EPC (Ser1177). In light of these observations, we postulated that the heterotrimeric serine/threonine kinase, AMPK, may play a role in triggering the development of the anti-inflammatory phenotype induced by EPC. Ethanol was administered to C57BL/6J mice by gavage in the presence or absence of AMPK inhibition. Twenty-four hours later, the numbers of rolling and adherent leukocytes in postcapillary venules of the small intestine were recorded using an intravital microscopic approach. Following 45 min of ischemia, LEI were recorded after 30 and 60 min of reperfusion or at equivalent time points in control animals. Ischemia-reperfusion induced a marked increase in LEI relative to sham-operated control mice. The increase in LEI was prevented by EPC, an effect that was lost with AMPK inhibition during the period of ethanol exposure. Studies conducted in AMPK α(1)- and α(2)-knockout mice suggest that the anti-inflammatory effects of AICAR are not dependent on which isoform of the catalytic α-subunit is present because a deficiency of either isoform results in a loss of protection. In sharp contrast, EPC appears to be triggered by an AMPK α(2)-isoform-dependent mechanism.
Departments of Medical Pharmacology and Physiology, University of Missouri, Columbia, 65212, USA.
F Spencer
FS
Gaskin
Kazuhiro
K
Kamada
Mozow Yusof
MY
Zuidema
Allan W
AW
Jones
Leona J
LJ
Rubin
Ronald J
RJ
Korthuis
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology; D007421:Intestine, Small / Q000098:blood supply / Q000187:drug effects; D019194:Ischemic Preconditioning / Q000379:methods*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D012265:Ribonucleotides / Q000494:pharmacology; D014699:Venules / Q000187:drug effects
D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000431:Ethanol; D017868:Cyclic AMP-Dependent Protein Kinases; C031143:AICA ribonucleotide
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