A novel sphingosine-1-phosphate receptor agonist KRP-203 attenuates rat autoimmune myocarditis.
Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the treatment of rat experimental autoimmune myocarditis. KRP-203 significantly attenuated the inflammation area, heart weight/body weight ratio, and left ventricular function. Immunohistochemical analysis and RT-PCR revealed that KRP-203 significantly decreased the infiltration of macrophages and CD4 T cells in the myocardium and the expression of inflammatory cytokines. Flow cytometric analysis revealed that treatment with KRP-203 effectively reduced the number of peripheral CD4 and CD8 T cells but not that of B cells and granulocytes. Further, late KRP-203 treatment was effective even against established EAM. These results demonstrate the therapeutic potential of KRP-203 for the treatment of human myocarditis and provide new insights into the pathogenesis of this disease.
Ogawa
Ryo
R
Division of Cardiovascular Sciences, Department of Organ Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Takahashi
Masafumi
M
Hirose
Sho-Ichi
S
Morimoto
Hajime
H
Ise
Hirohiko
H
Murakami
Takashi
T
Yasue
Tokutaro
T
Kuriyama
Kazuhiko
K
Hongo
Minoru
M
Kobayashi
Eiji
E
Ikeda
Uichi
U
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D001835:Body Weight; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D016207:Cytokines; C501899:KRP-203; D049349:Receptors, Lysosphingolipid; D013438:Sulfhydryl Compounds