Faculty Collaboration Database

Cyclooxygenase-1 and -2 knockout mice demonstrate increased cardiac ischemia/reperfusion injury but are protected by acute preconditioning. Circulation 2001 Nov 13;104(20):2453-8

Date

11/14/2001

Pubmed ID

11705824

DOI

10.1161/hc4401.098429

Scopus ID

2-s2.0-0035856556 (requires institutional sign-in at Scopus site)   88 Citations

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(-/-) mice, baseline cardiac prostaglandin (PG) E(2) and 6-keto-PGF(1alpha) levels were significantly decreased in hearts from COX-1(-/-) mice. After ischemia, cardiac PGE(2) levels increased in WT, COX-1(-/-), and COX-2(-/-) mice (P<0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1(-/-) and COX-2(-/-) 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(-/-) and COX-2(-/-) was unchanged by perfusion with 5 micromol/L PGE(2), PGD(2), PGF(2alpha), or carboprostacyclin. Hearts from COX-2(-/-) mice showed an increase in ischemic contracture compared with hearts from WT and COX-1(-/-) 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(-/-), COX-2(-/-), 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.

Author List

Camitta MG, Gabel SA, Chulada P, Bradbury JA, Langenbach R, Zeldin DC, Murphy E

MESH terms used to index this publication - Major topics in bold

Animals
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Hemodynamics
Hydrogen-Ion Concentration
Indomethacin
Ischemic Preconditioning, Myocardial
Isoenzymes
Kinetics
Membrane Proteins
Mice
Mice, Knockout
Myocardial Contraction
Myocardial Reperfusion Injury
Organ Culture Techniques
Phosphates
Prostaglandin-Endoperoxide Synthases
Prostaglandins
Ventricular Pressure