Cyclooxygenase-1 and -2 Knockout Mice Demonstrate Increased Cardiac Ischemia/Reperfusion Injury but Are Protected by Acute Preconditioning

Abstract

Background-The purpose of this study was to examine the effects of cyclooxygenase (COX) deficiency on baseline functional characteristics and on recovery of left ventricular developed pressure (LVDP) after 20 minutes of global ischemia and 40 minutes of reperfusion in untreated and preconditioned hearts. Methods and Results-Compared with hearts from wild-type (WT) and COX-2 Ϫ/Ϫ mice, baseline cardiac prostaglandin (PG) E 2 and 6-keto-PGF 1␣ levels were significantly decreased in hearts from COX-1 Ϫ/Ϫ mice. After ischemia, cardiac PGE 2 levels increased in WT, COX-1 Ϫ/Ϫ , and COX-2 Ϫ/Ϫ mice (PϽ0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1 Ϫ/Ϫ and COX-2 Ϫ/Ϫ mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia significantly decreased LVDP recovery; however, perfusion of WT hearts with indomethacin for 40 minutes before ischemia did not significantly alter LVDP recovery. Postischemic recovery of LVDP in COX-1 Ϫ/Ϫ and COX-2 Ϫ/Ϫ was unchanged by perfusion with 5 mol/L PGE 2 , PGD 2 , PGF 2␣ , or carboprostacyclin. Hearts from COX-2 Ϫ/Ϫ mice showed an increase in ischemic contracture compared with hearts from WT and COX-1 Ϫ/Ϫ mice; however, hearts did not differ in intracellular pH, ATP, or inorganic phosphate during ischemia. Ischemic preconditioning significantly improved postischemic LVDP recovery in COX-1 Ϫ/Ϫ , COX-2 Ϫ/Ϫ , and WT mice. Conclusions-Genetic disruption or 2-day chemical inhibition of COX-1 and COX-2 decreases recovery of LVDP after ischemia; however, acute perfusion with indomethacin is not detrimental. These data are consistent with protection due to the altered expression of some protein that is modulated by COX or its metabolites.

Cardioprotection by Adiponectin

“…Cyclooxygenase-2 and its metabolites have been shown to be required for late preconditioning and play important protective roles in myocardial ischemia-reperfusion damage (Bolli et al 2002, Camitta et al 2001, Hohlfeld et al 2000, Xiao et al 2001, Xiao et al 2004. Recent clinical trials reveal that treatment with selective COX-2 inhibitors results in an increased risk for cardiovascular complications including myocardial infarction (Bresalier et al 2005, Solomon et al 2005.…”

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

“…In cardiomyocytes, glucocorticoids have been found to protect cells from apoptosis . Since prostaglandins have been shown to elicit a cardiac protective effect against oxidant, doxorubicin, or ischemia-reperfusion induced injury (Adderley and Fitzgerald, 1999;Camitta et al, 2001;Bolli et al, 2002;Calabresi et al, 2003;Xiao et al, 2004;Shinmura et al, 2005), induction of COX-2 may serve as an important mechanism of glucocorticoid induced cytoprotection. The goal of this study is to address whether PI3K plays a role in CT induced COX-2 expression.…”

COX-2-dependent and potentially cardioprotective effects of negative inotropic substances released after ischemia

“…A concentration of prostaglandins in cells increases under postischemic conditions (27). An inhibition of COX by indomethacin leads to a reduction in cardioprotection after ischemia (5). It has been speculated that a yet unknown cardioprotective factor is metabolized by COX.…”