Inducible nitric oxide synthase modulates cyclooxygenase-2 activity in the heart of conscious rabbits during the late phase of ischemic preconditioning

被引:139
作者
Shinmura, K
Xuan, YT
Tang, XL
Kodani, E
Han, H
Zhu, YQ
Bolli, R [1 ]
机构
[1] Univ Louisville, Div Cardiol, Expt Res Lab, Louisville, KY 40292 USA
[2] Jewish Hosp Heart, Louisville, KY USA
[3] Lung Inst, Louisville, KY USA
关键词
prostaglandins; myocardial ischemia; reperfusion;
D O I
10.1161/01.RES.0000012202.52809.40
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Cyclooxygenase-2 (COX-2) is known to mediate the cardioprotective effects of the late phase of ischemic preconditioning (PC); however, the signaling pathways involved in COX-2 induction following ischemic PC are unknown. In addition, although inducible nitric oxide synthase (iNOS) has been identified as a co-mediator of late PC together with COX-2, the interaction between iNOS and COX-2 in the heart is unknown. Using conscious rabbits, we found that the induction of COX-2 expression 24 hours after ischemic PC was blocked by pretreatment with inhibitors of protein kinase C (PKC), Src protein tyrosine kinases (PTKs), and nuclear factor-kappaB (NF-kappaB) but not by inhibitors of NOS or scavengers of reactive oxygen species (ROS). The selective iNOS inhibitors SMT and 1400W, given 24 hours after PC, abrogated the increase in myocardial prostaglandin E-2 (PGE(2)) and 6-keto-PGF(1alpha), whereas the selective soluble guanylate cyclase inhibitor ODQ had no effect. COX-2 selective inhibitors (celecoxib and NS-398) did not affect iNOS activity. These results demonstrate that (i) ischemic PC upregulates cardiac COX-2 via PKC-, Src PTK-, and NF-kappaB-dependent signaling pathways, whereas generation of NO and ROS is not necessary, and (ii) the activity of newly synthesized COX-2 following PC requires iNOS-derived NO whereas iNOS activity is independent of COX-2-derived prostanoids, indicating that COX-2 is located downstream of iNOS in the protective pathway of late PC. The data also indicate that iNOS modulates COX-2 activity via cGMP-independent mechanisms. To our knowledge, this is the first demonstration that iNOS-derived NO drives prostanoid synthesis by COX-2 in the heart. NO-mediated activation of COX-2 may be a heretofore unrecognized mechanism by which NO exerts its salubrious effects in the late phase of PC.
引用
收藏
页码:602 / 608
页数:7
相关论文
共 41 条
[1]   Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2 [J].
Adderley, SR ;
Fitzgerald, DJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (08) :5038-5046
[2]   Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage - Influence of nitric oxide [J].
Amin, AR ;
Attur, M ;
Patel, RN ;
Thakker, GD ;
Marshall, PJ ;
Rediske, J ;
Stuchin, SA ;
Patel, IR ;
Abramson, SB .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (06) :1231-1237
[3]   Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C mitogen-activated protein kinase-dependent pathway [J].
Barry, OP ;
Kazanietz, MG ;
Praticò, D ;
FitzGerald, GA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (11) :7545-7556
[4]   INVOLVEMENT OF TYROSINE KINASES IN THE INDUCTION OF CYCLO-OXYGENASE-2 IN HUMAN ENDOTHELIAL CELLS [J].
BLANCO, A ;
HABIB, A ;
LEVYTOLEDANO, S ;
MACLOUF, J .
BIOCHEMICAL JOURNAL, 1995, 312 :419-423
[5]   The late phase of preconditioning [J].
Bolli, R .
CIRCULATION RESEARCH, 2000, 87 (11) :972-983
[6]   Evidence that late preconditioning against myocardial stunning in conscious rabbits is triggered by the generation of nitric oxide [J].
Bolli, R ;
Bhatti, ZA ;
Tang, XL ;
Qiu, YM ;
Zhang, Q ;
Guo, Y ;
Jadoon, AK .
CIRCULATION RESEARCH, 1997, 81 (01) :42-52
[7]  
Bolli R, 1997, CIRC RES, V81, P1094
[8]   RADICICOL, A PROTEIN-TYROSINE KINASE INHIBITOR, SUPPRESSES THE EXPRESSION OF MITOGEN-INDUCIBLE CYCLOOXYGENASE IN MACROPHAGES STIMULATED WITH LIPOPOLYSACCHARIDE AND IN EXPERIMENTAL GLOMERULONEPHRITIS [J].
CHANMUGAM, P ;
FENG, LL ;
LIOU, SE ;
JANG, BOC ;
BOUDREAU, M ;
YU, G ;
LEE, JH ;
KWON, HJ ;
BEPPU, T ;
YOSHIDA, M ;
XIA, YY ;
WILSON, CB ;
HWANG, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (10) :5418-5426
[9]   Nitric oxide synthase/COX cross-talk: Nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production [J].
Clancy, R ;
Varenika, B ;
Huang, WQ ;
Ballou, L ;
Attur, M ;
Amin, AR ;
Abramson, SB .
JOURNAL OF IMMUNOLOGY, 2000, 165 (03) :1582-1587
[10]   Nitric oxide: A prostaglandin H synthase 1 and 2 reducing cosubstrate that does not stimulate cyclooxygenase activity or prostaglandin H synthase expression in murine macrophages [J].
Curtis, JF ;
Reddy, NG ;
Mason, RP ;
Kalyanaraman, B ;
Eling, TE .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1996, 335 (02) :369-376