Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury.
OBJECTIVE
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 PGE2 (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 A2 (cPLA2) (174.8+/-0.5%), COX2 (446.2+/-0.9%), PGI2 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.
Birnbaum
Yochai
Y
The Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, 5,106 John Sealy Annex, 301 University Blvd., Galveston, Texas 77555-0553, USA. yobirnba@utmb.edu
Ye
Yumei
Y
Rosanio
Salvatore
S
Tavackoli
Shahin
S
Hu
Zhao-Yong
ZY
Schwarz
Ernst R
ER
Uretsky
Barry F
BF
D000818:Animals; D000069059:Atorvastatin; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000502:physiology*; D011758:Pyrroles / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D000069059:Atorvastatin; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019746:Intramolecular Oxidoreductases; D007555:Isoxazoles; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010741:Phospholipases A; D054467:Phospholipases A2; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D011758:Pyrroles; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C489691:Ptgs2 protein, rat; C022461:prostacyclin synthetase