Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury

Objectives: Statins attenuate myocardial ischemic injury by activating nitric oxide synthase (NOS). It is unknown whether cyclooxygenase-2 (COX2), which mediates late ischemic preconditioning, also mediates statins-induced cardioprotection. We investigated the involvement of the prostaglandins and NOS in the cardioprotective effect of atorvastatin (ATV) in the rat. Methods: Sprague-Dawley rats were randomized to a 3-day oral treatment with ATV 10 mg/kg, valdecoxib, a selective COX2 inhibitor (VAL) 3 mg/kg, ATV+VAL or water alone. Rats underwent 30-min myocardial ischemia followed by 4-h reperfusion. Results: Infarct size was smaller in the ATV group (31.3 +/- 1.9%) than controls (44.5 +/- 3.1%; p=0.011) and VAL (44.5 +/- 3.1%; p=0.008). VAL attenuated the protective effect of ATV when administered together (40.2 +/- 2.5%). ATV pretreatment increased myocardial content of 6-keto-PGF(1alpha) (69.5 +/- 1.5 pg/mg) and PGE(2) (57.9 +/- 0.6 pg/mg) compared with controls (16.2 +/- 0.2 and 42.1 +/- 2.0 pg/mg, respectively) and ATV+VAL (15.8 +/- 0.3 and 39.9 +/- 1.9 pg/mg, respectively). ATV increased myocardial content of cytosolic phospholipase A(2) (cPLA(2)) (174.8 +/- 0.5%) COX2 (446.2 +/- 0.9%), PGI(2) synthase (201.8 +/- 1.1%) and PGE2 synthase (122 +/- 0.7%), whereas ATV+VAL did not (123.0 +/- 7.9%, 93.8 +/- 8.5%, 103.0 +/- 1.6% and 99.0 +/- 0%, respectively). ATV did not change the myocardial content of eNOS and nNOS, but increased the concentration of phosphorylated eNOS (231.8 +/- 2.4%) and iNOS (154.5 +/- 1.2%). This effect was not blocked by coadministration of VAL (231.5 +/- 3.0% and 154.5 +/- 1.8%, respectively). Conclusions: Our results suggest that the prostaglandins are essential for mediating the myocardial protective effects of ATV and their production is downstream to eNOS phosphorylation and iNOS. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.