Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia.
OBJECTIVE
The objective of the present study is to elucidate the pathogenic role of eicosanoids in myocardial infarction (MI). The accumulation of eicosanoid metabolites in ischaemic myocardium has been demonstrated in animal models and patients with MI, and it occurs in parallel with the development of irreversible cardiac damage. However, the key question that remains unanswered is whether cardiac-generated eicosanoids are the cause or the consequence of cardiac cell damage in MI.


RESULTS
We used a clinically relevant animal model of MI and metabolic profiling to monitor the eicosanoid profile in ischaemic myocardium. We demonstrate that ischaemia induces the generation of prostanoids mainly through the cyclooxygenase (COX)-1 pathway in the myocardium. Cardiac-generated prostanoids, particularly prostaglandin D(2) (PGD(2)), can directly induce apoptosis in cardiac myocytes. This effect involves the up-regulation of the pro-apoptotic gene, Fas ligand (FasL), in a D-type prostanoid receptor-independent manner. The treatment of the MI mice with low-dose aspirin effectively inhibits the ischaemia-induced prostanoid generation and FasL expression in the myocardium, leading to the reduction in cardiac apoptosis following cardiac ischaemia.


CONCLUSIONS
Cardiac ischaemia results in COX-1-mediated generation of prostanoids, which by inducing cardiac myocyte apoptosis, contribute to the cardiac cell loss following MI. The benefits of low-dose aspirin treatment in MI may be attributable, in part, to the inhibition of cardiac prostanoid generation and attenuation of apoptosis. Further understanding of the mechanisms underlying prostanoid-induced cardiac apoptosis may be of significant value in designing new therapeutic strategies to prevent aberrant cell loss following MI and subsequent progression to heart failure.
Division of Cardiovascular Medicine, Department of Internal Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Hong
H
Qiu
Jun-Yan
JY
Liu
Dongguang
D
Wei
Ning
N
Li
Ebenezer N
EN
Yamoah
Bruce D
BD
Hammock
Nipavan
N
Chiamvimonvat
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015230:Prostaglandin D2 / Q000378:metabolism; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left
D016861:Cyclooxygenase Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008565:Membrane Proteins; D011453:Prostaglandins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D001241:Aspirin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor