The endothelial-protective effects of HMG-CoA reductase inhibition in the setting of ischemia and reperfusion injury.
Animal studies have consistently demonstrated the ability of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors to limit the damage induced by ischemia-reperfusion (IR) in the cardiac, cerebral and mesenteric circulation through a mechanism dependent on the upregulation of cyclooxygenase-2 (COX-2). Our group performed studies aimed at investigating the mechanism of HMG-CoA reductase inhibitor-mediated endothelial protection from IR injury, in particular the role of COX-2, in a human in vivo model of IR-induced endothelial dysfunction. We demonstrated that HMG-CoA reductase inhibition protects against IR-induced endothelial damage, an effect that was lost upon COX-2 inhibition. These observations may suggest a mechanistic explanation for the cardioprotection observed in clinical settings such as percutaneous coronary interventions and coronary artery bypass surgery and may also propose a mechanistic hypothesis for the reported cardiotoxic effects of cyclooxygenase-2 inhibitors observed in clinical studies. These studies are summarized and discussed in the present paper.
Liuni
Andrew
A
Division of Cardiology, Mount Sinai and University Health Network Hospitals, Department of Pharmacology, University of Toronto, Canada.
Luca
Mary Clare
MC
Gori
Tommaso
T
Parker
John D
JD
D051546:Cyclooxygenase 2 / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020011:Protective Agents; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D051546:Cyclooxygenase 2