Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway.
OBJECTIVE
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 micromol/l (optimal protection was seen at 50 micromol/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.
Bell
Robert M
RM
The Hatter Institute for Cardiovascular Studies, Academic and Clinical Cardiology, Division of Medicine, University College Hospitals and Medical School, University College London, Grafton Way, London WC1E 6DB, UK. hatter-institute@ucl.ac.uk
Yellon
Derek M
DM
D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000008:administration & dosage* / Q000627:therapeutic use*; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D000069059:Atorvastatin; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011758:Pyrroles