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Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway

Bell, RM; Yellon, DM; (2003) Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J AM COLL CARDIOL , 41 (3) 508 - 515. 10.1016/S0735-1097(02)02816-4.

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Abstract

OBJECTIVES The purpose of this study was to determine whether atorvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-co-enzyme A (CoA) reductase inhibitor, limits myocardial necrosis when administered as an adjunct to reperfusion.BACKGROUND Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol. However, it is proposed that statins have cardiovascular effects beyond their ability to lower cholesterol, possibly via recruitment of phosphatidyl inositol 3-kinase (PI3K) and the serine/threonine kinase, Akt. This signaling pathway has recently been linked to growth factor-mediated reperfusion salvage.*METHODS Isolated perfused mouse hearts were subjected to 35 min of global ischemia and reperfused for 30 min in the presence of incremental concentrations of atorvastatin. Infarct size was determined by triphenyltetrazolium chloride staining, and the activity of the PI3K signaling cascade was determined by Western blot analysis.RESULTS We found that there was a profound dose-dependent reduction of infarct size with atorvastatin in the range of 25 to 100 mumol/l (optimal protection was seen at 50 mumol/l with infarct size of 16 +/- 2% vs. control, 33 +/- 2%, p < 0.01). Moreover, this protection was sensitive to inhibition with the PI3 kinase inhibitor, wortmannin, and was absent in endothelial nitric oxide synthase (eNOS) knockout mice. Western blot analysis revealed that atorvastatin resulted in rapid activation of the PI3K/Akt signaling cascade (within 5 min) and that both Akt and eNOS phosphorylation were significantly increased by 4.1-fold and 2.9-fold, respectively (p < 0.01). Moreover, phosphorylation of the PI3K substrates was abrogated by the administration of wortmannin.CONCLUSIONS Atorvastatin attenuates lethal reperfusion-induced injury in a manner that is reliant on PI3K and Akt activity and the presence and activity of eNOS.

Type:Article
Title:Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway
DOI:10.1016/S0735-1097(02)02816-4
Keywords:NITRIC-OXIDE SYNTHASE, RAT HEARTS, INJURY, AKT, ISCHEMIA, PRAVASTATIN, ACTIVATION, KINASE, PHOSPHORYLATION, INHIBITION
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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