title: Preserved heart function and maintained response to cardiac stresses in a genetic model of cardiomyocyte-targeted deficiency of cyclooxygenase-2.
abstract: 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.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Kyriakos N
authors.initials: KN
authors.lastname: Papanicolaou
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.forename: Tomo-O
authors.initials: TO
authors.lastname: Ishikawa
authors.forename: Harvey
authors.initials: H
authors.lastname: Herschman
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: 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
chemical_list: C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C045073:Cre recombinase; D019426:Integrases
references.citation: Circulation. 2001 Nov 13;104(20):2453-8
references.pmid: 11705824
references.citation: Circ Res. 2009 Jul 2;105(1):12-5
references.pmid: 19520971
references.citation: Hypertension. 2002 Feb;39(2 Pt 2):382-8
references.pmid: 11882577
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):20009-14
references.pmid: 19060214
references.citation: J Mol Cell Cardiol. 2010 Jul;49(1):88-94
references.pmid: 20170663
references.citation: Cardiovasc Res. 2002 Aug 15;55(3):506-19
references.pmid: 12160947
references.citation: J Mol Cell Cardiol. 2007 Jun;42(6):1065-74
references.pmid: 17499764
references.citation: Circulation. 2007 Jan 23;115(3):326-32
references.pmid: 17210840
references.citation: Circ Res. 2009 Dec 4;105(12):1164-76
references.pmid: 19959782
references.citation: Nat Med. 2004 Dec;10(12):1384-9
references.pmid: 15558058
references.citation: Life Sci. 2005 Nov 26;78(2):195-204
references.pmid: 16107267
references.citation: Nat Med. 2005 Oct;11(10):1096-103
references.pmid: 16155579
references.citation: Circulation. 2009 Oct 20;120(16):1606-15
references.pmid: 19805648
references.citation: Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1330-7
references.pmid: 16697347
references.citation: Nature. 1995 Nov 23;378(6555):406-9
references.pmid: 7477380
references.citation: Am J Physiol. 1995 Jan;268(1 Pt 2):H308-15
references.pmid: 7840277
references.citation: Congest Heart Fail. 1999 Sep-Oct;5(5):222-227
references.pmid: 12189304
references.citation: Mol Cell Biol. 2009 Jul;29(13):3487-99
references.pmid: 19398582
references.citation: Basic Res Cardiol. 2000 Dec;95(6):479-84
references.pmid: 11192369
references.citation: Circ Res. 2010 Jan 8;106(1):47-57
references.pmid: 20056945
references.citation: Dev Cell. 2009 Feb;16(2):233-44
references.pmid: 19217425
references.citation: Circulation. 2004 Mar 23;109(11):1428-33
references.pmid: 15023870
references.citation: Neuron. 1993 Aug;11(2):371-86
references.pmid: 8352945
references.citation: J Biol Chem. 1998 Jan 9;273(2):1252-6
references.pmid: 9422794
references.citation: Circulation. 2007 Oct 2;116(14):1577-84
references.pmid: 17785622
references.citation: Cell. 1999 Feb 5;96(3):307-10
references.pmid: 10025395
references.citation: Cell. 1997 Oct 17;91(2):197-208
references.pmid: 9346237
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7548-52
references.pmid: 19376970
references.citation: J Mol Cell Cardiol. 2009 Feb;46(2):130-6
references.pmid: 18845155
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2878-83
references.pmid: 11854453
references.citation: N Engl J Med. 2004 Oct 21;351(17):1709-11
references.pmid: 15470192
references.citation: Circulation. 1998 Jul 14;98(2):100-3
references.pmid: 9679714
references.citation: Prostaglandins Leukot Essent Fatty Acids. 1995 Sep;53(3):197-200
references.pmid: 7480082
references.citation: Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1416-24
references.pmid: 14670812
references.citation: JAMA. 2001 Aug 22-29;286(8):954-9
references.pmid: 11509060
references.citation: Circulation. 2001 Oct 30;104(18):2210-5
references.pmid: 11684633
references.citation: Heart. 2004 Apr;90(4):440-3
references.pmid: 15020525
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10197-202
references.pmid: 10963682
references.citation: J Clin Invest. 2006 May;116(5):1391-9
references.pmid: 16614756
references.citation: J Clin Invest. 1997 Jul 1;100(1):169-79
references.pmid: 9202069
references.citation: Cell. 1995 Nov 3;83(3):473-82
references.pmid: 8521477
references.citation: J Biol Chem. 2004 Jun 11;279(24):25219-25
references.pmid: 15070903
references.citation: Circulation. 2000 Feb 1;101(4):430-8
references.pmid: 10653836
references.citation: Am J Physiol Renal Physiol. 2005 Jun;288(6):F1125-32
references.pmid: 15613621
references.citation: J Biol Chem. 2001 Apr 13;276(15):12035-40
references.pmid: 11134037
references.citation: Annu Rev Biochem. 2000;69:145-82
references.pmid: 10966456
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2148-54
references.pmid: 17660401
references.citation: Biochem Biophys Res Commun. 2000 Jul 5;273(2):772-5
references.pmid: 10873679
references.citation: Curr Opin Cell Biol. 2004 Jun;16(3):293-9
references.pmid: 15145354
references.citation: Circulation. 2004 May 25;109(20):2462-8
references.pmid: 15123528
references.citation: Nature. 2000 May 4;405(6782):97-101
references.pmid: 10811226
references.citation: Cardiovasc Hematol Agents Med Chem. 2008 Jan;6(1):69-79
references.pmid: 18220723
references.citation: J Clin Invest. 2006 Jan;116(1):4-15
references.pmid: 16395396
references.citation: J Cardiovasc Pharmacol. 2009 Jun;53(6):495-8
references.pmid: 19455055
references.citation: Annu Rev Biophys Biomol Struct. 2003;32:183-206
references.pmid: 12574066
references.citation: Pharmacol Rev. 2004 Sep;56(3):387-437
references.pmid: 15317910
references.citation: J Clin Invest. 1994 Dec;94(6):2504-10
references.pmid: 7989609
references.citation: Circ Res. 2008 Apr 11;102(7):752-60
references.pmid: 18296617
references.citation: Circulation. 2008 Apr 22;117(16):2114-22
references.pmid: 18391113
references.citation: Science. 2002 Apr 19;296(5567):539-41
references.pmid: 11964481
references.citation: Cell Metab. 2005 Sep;2(3):201-7
references.pmid: 16154102
references.citation: Am J Physiol Heart Circ Physiol. 2005 May;288(5):H2111-7
references.pmid: 15626689
references.citation: J Mol Cell Cardiol. 2004 Jul;37(1):71-7
references.pmid: 15242737
references.citation: Genesis. 2006 Mar;44(3):143-9
references.pmid: 16496341
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7985-90
references.pmid: 19416858
references.citation: Pflugers Arch. 2008 Mar;455(6):971-8
references.pmid: 17901979
references.citation: N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528
references.pmid: 11087881
references.citation: N Engl J Med. 2005 Mar 17;352(11):1071-80
references.pmid: 15713944
references.citation: J Clin Invest. 2001 Aug;108(4):585-90
references.pmid: 11518732
references.citation: Physiol Rev. 1999 Oct;79(4):1193-226
references.pmid: 10508233
references.citation: Am J Med. 1999 May 31;106(5B):37S-42S
references.pmid: 10390126
references.citation: Nat Protoc. 2008;3(9):1422-34
references.pmid: 18772869
references.citation: Circ Res. 2007 Aug 3;101(3):313-21
references.pmid: 17569887
references.citation: J Cardiovasc Pharmacol. 2007 Jun;49(6):416-8
references.pmid: 17577107
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):272-7
references.pmid: 9874808
references.citation: FEBS Lett. 2008 Apr 2;582(7):1147-50
references.pmid: 18339320
references.citation: N Engl J Med. 2005 Mar 17;352(11):1092-102
references.pmid: 15713943
references.citation: J Clin Invest. 2004 Sep;114(6):784-94
references.pmid: 15372102
references.citation: Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H532-6
references.pmid: 16617129
references.citation: J Mol Cell Cardiol. 2009 Feb;46(2):160-8
references.pmid: 19084534
references.citation: J Biol Chem. 1999 Feb 19;274(8):5038-46
references.pmid: 9988750
references.citation: J Biol Chem. 1997 Aug 22;272(34):21565-74
references.pmid: 9261177