FR167653 suppresses the progression of experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) induced in rats by injection of cardiac myosin is an animal model of human myocarditis and post-myocarditis dilated cardiomyopathy. It has been reported that proinflammatory cytokines play crucial roles in the induction of EAM and in the progression of myocardial injury in this disease. FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl) pyrazolo [5,1-c] [1,2,4] triazin-2-yl]-2-phenylethanedione sulfate monohydrate) as been reported to suppress tumor necrosis factor-alpha (TNF-alpha). We hypothesized that FR167653 would suppress the progression of EAM if TNF-alpha and/or interleukin-1 beta (IL-1beta) were the culprit cytokines in EAM. To investigate the effects of FR167653 in EAM, FR167653 was given to rats for 4 weeks, immediately after they had been immunized with cardiac myosin. The ratio of heart weight to body weight and the area of inflammatory lesions were less in the FR167653 groups than in the control rats. FR167653 reduced serum sialic acid levels significantly. The control group showed a deterioration in cardiac function. The FR167653 groups had significantly better hemodynamic parameters, including improved left ventricular end-diastolic pressure, central venous pressure, aortic pressure, and positive and negative left ventricular pressure derivatives. mRNA expression of IL-1beta in the heart was significantly lower in rats given FR167653. However, mRNA of TNF-alpha was not detected in any groups. Our results suggest that FR167653 suppresses the development of myocarditis by suppression of IL-1beta.
Maruyama
Seitaro
S
First Department of Internal Medicine, Institute of Nephrology, Niigata University School of Medicine, Niigata, Japan. maruyama@med.niigata-u.ac.jp
Kato
Kiminori
K
Kodama
Makoto
M
Okura
Yuji
Y
Hirono
Satoru
S
Fuse
Koichi
K
Hanawa
Haruo
H
Nakagawa
Osamu
O
Nakazawa
Mikio
M
Miida
Takashi
T
Yaoita
Eisin
E
Yamamoto
Tadashi
T
Inoue
Ikuo
I
Aizawa
Yoshifusa
Y
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D024722:Cardiac Myosins / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C104334:FR 167653; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D024722:Cardiac Myosins