prostaglandin-d2 and Myocardial-Ischemia

The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIα subunit (PRKAR2A) to the transmembrane domain of IFN-γ receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRKAR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD2-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRKAR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation-associated diseases, including post-MI healing.

Topics: Animals; Cecum; Cell Polarity; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; Disease Models, Animal; Female; Gene Deletion; Hydantoins; Inflammation; Janus Kinase 2; Ligation; Macrophages; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Ischemia; Peritonitis; Prostaglandin D2; Protein Binding; Protein Subunits; Punctures; Receptors, Immunologic; Receptors, Interferon; Receptors, Prostaglandin; Signal Transduction; STAT1 Transcription Factor; Wound Healing; Zymosan

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.. 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.. 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.

Topics: Animals; Animals, Newborn; Apoptosis; Aspirin; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Disease Models, Animal; Fas Ligand Protein; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocardium; Prostaglandin D2; Prostaglandins; Receptors, Immunologic; Receptors, Prostaglandin; RNA, Messenger; Time Factors; Up-Regulation; Ventricular Function, Left