Preserved heart function and maintained response to cardiac stresses in a genetic model of cardiomyocyte-targeted deficiency of cyclooxygenase-2.
Cyclooxygenase-1 and -2 are rate-limiting enzymes in the formation of a wide array of bioactive lipid mediators collectively known as prostanoids (prostaglandins, prostacyclins, and thromboxanes). Evidence from clinical trials shows that selective inhibition of the second isoenzyme (cyclooxygenase-2, or Cox-2) is associated with increased risk for serious cardiovascular events and findings from animal-based studies have suggested protective roles of Cox-2 for the heart. To further characterize the function of Cox-2 in the heart, mice with loxP sites flanking exons 4 and 5 of Cox-2 were rendered knockout specifically in cardiac myocytes (Cox-2 CKO mice) via cre-mediated recombination. Baseline cardiac performance of CKO mice remained unchanged and closely resembled that of control mice. Furthermore, myocardial infarct size induced after in vivo ischemia/reperfusion (I/R) injury was comparable between CKO and control mice. In addition, cardiac hypertrophy and function four weeks after transverse aortic constriction (TAC) was found to be similar between the two groups. Assessment of Cox-2 expression in purified adult cardiac cells isolated after I/R and TAC suggests that the dominant source of Cox-2 is found in the non-myocyte fraction. In conclusion, our animal-based analyses together with the cell-based observations portray a limited role of cardiomyocyte-produced Cox-2 at baseline and in the context of ischemic or hemodynamic challenge.
Papanicolaou
Kyriakos N
KN
Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
Streicher
John M
JM
Ishikawa
Tomo-O
TO
Herschman
Harvey
H
Wang
Yibin
Y
Walsh
Kenneth
K
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology*; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009928:Organ Specificity; D011312:Pressure; D011995:Recombination, Genetic / Q000235:genetics; D013312:Stress, Physiological; D013599:Systole / Q000502:physiology
C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C045073:Cre recombinase; D019426:Integrases
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