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.
Division of Cardiovascular Sciences, Department of Organ Regeneration, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Ryo
R
Ogawa
Masafumi
M
Takahashi
Sho-Ichi
S
Hirose
Hajime
H
Morimoto
Hirohiko
H
Ise
Takashi
T
Murakami
Tokutaro
T
Yasue
Kazuhiko
K
Kuriyama
Minoru
M
Hongo
Eiji
E
Kobayashi
Uichi
U
Ikeda
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