Inhibition of cyclooxygenase-2 enhances myocardial damage in a mouse model of viral myocarditis.
To determine critical role of cyclooxygenase-2 (COX-2) for development of viral myocarditis, a mouse model of encephalomyocarditis virus-induced myocarditis was used. The virus was intraperitoneally given to COX-2 gene-deficient heterozygote mice (COX-2+/-) and wild-type mice (WT). We examined differences in heart weights, cardiac histological scores, numbers of infiltrating or apoptotic cells in myocardium, cardiac expression levels of COX-2, tumor necrosis factor-alpha (TNF-alpha), and adiponectin mRNA, immunoreactivity of COX-2, TNF-alpha, and adiponectin in myocytes, cardiac concentrations of TNF-alpha and adiponectin, prostaglandin E2 (PGE2) levels in hearts, and viral titers in tissues between COX-2+/- and WT. We observed significantly decreased expression of COX-2 mRNA and reactivity in hearts from COX-2+/- on day 8 after viral inoculation as compared with that from WT, together with elevated cardiac weights and severe inflammatory myocardial damage in COX-2+/-. Cardiac expression of TNF-alpha mRNA, reactivity, and protein on day 8 was significantly higher in COX-2+/- than in WT, together with reciprocal expression of adiponectin mRNA, reactivity, and protein in hearts. Significantly reduced cardiac PGE2 levels on day 8 were found in COX-2+/- compared with those in WT. There was no difference in local viral titers between both groups on day 4. Infected WT treated with a selective COX-2 inhibitor, NS-398, also showed the augmented myocardial damage on day 8. These results suggest that inhibition of COX-2 may enhance myocardial damage through reciprocal cardiac expression of TNF-alpha and adiponectin in a mouse model of viral myocarditis.
Takahashi
Takashi
T
Department of a General Medicine, Kanazawa Medical University, Uchinada-machi, Kahoku-gun, Ishikawa 920-0293, Japan.
Zhu
Shi-jie
SJ
Sumino
Hiroyuki
H
Saegusa
Seiichiro
S
Nakahashi
Takeshi
T
Iwai
Kunimitsu
K
Morimoto
Shigeto
S
Kanda
Tsugiyasu
T
D052242:Adiponectin / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000502:physiology; D018188:Cardiovirus Infections / Q000201:enzymology / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D004686:Encephalomyocarditis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology / Q000821:virology; D009578:Nitrobenzenes / Q000494:pharmacology; D009929:Organ Size / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D052242:Adiponectin; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone