Inhibition of prostaglandin D synthase suppresses muscular necrosis.
Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D(2). In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D(2) signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy. We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor beta1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D(2) production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy.
Department of Molecular Behavioral Biology, Molecular Research Center for Child Mental Development, Osaka Bioscience Institute, Suita, Osaka, Japan.
Ikuko
I
Mohri
Kosuke
K
Aritake
Hidetoshi
H
Taniguchi
Yo
Y
Sato
Shinya
S
Kamauchi
Nanae
N
Nagata
Toshihiko
T
Maruyama
Masako
M
Taniike
Yoshihiro
Y
Urade
D000779:Anesthetics, Local / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002045:Bupivacaine / Q000633:toxicity; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054834:Lipocalins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D009336:Necrosis; D010880:Piperidines / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D000779:Anesthetics, Local; D016207:Cytokines; D054834:Lipocalins; D010880:Piperidines; D012333:RNA, Messenger; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; D002045:Bupivacaine