Experimental study
Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway

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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 μmol/l (optimal protection was seen at 50 μmol/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.

Abbreviations

AU
arbitrary units
DMSO
dimethyl sulfoxide
eNOS
endothelial nitric oxide synthase
HMG-CoA
3-hydroxy-3-methylglutaryl-co-enzyme A
KO
knockout
PI3K
phosphatidyl inositol 3-kinase
TTC
triphenyl tetrazolium chloride

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Supported by a grant from the British Heart Foundation. Robert M. Bell was supported by a clinical fellowship from Pfizer Pharmaceuticals.