A specific inhibitor of plasminogen activator inhibitor-1 suppresses rat autoimmune myocarditis.
OBJECTIVE
Myocarditis is a serious disease, however no effective treatment exists. Plasminogen activator inhibitor-1 (PAI-1) is critical in cell recruitment and inflammation. Although inflammation is an essential pathological feature of acute myocarditis, the effects of PAI-1 inhibition on the development of acute myocarditis have not been well studied.


METHODS
To clarify the role of PAI-1, we used a rat experimental autoimmune myocarditis (EAM) model. Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. The rats with induced EAM were treated with the PAI-1 inhibitor (IMD-1622) (n = 8) or not treated (n = 6); hearts were harvested on day 21. Echocardiograms, heart weight to body weight ratios (H:B), histological examinations and in vitro studies were performed.


RESULTS
Echocardiograms indicated that the PAI-1 inhibitor improved left ventricular fractional shortening (50 +/- 3%) compared with controls (36 +/- 4%, p < 0.05). The inhibitor significantly reduced H:B ratios compared with controls. Pathologically, areas of myocardial cell infiltration and fibrosis in the inhibitor-treated group were significantly smaller than those in the control group. Immunohistochemistry revealed enhanced expression of adhesion molecules and inflammatory factors in non-treated EAM hearts, the inhibitor suppressed this expression.


CONCLUSIONS
The PAI-1 inhibitor suppressed EAM development; thus this inhibitor is promising for treating clinical myocarditis.
Suzuki
Jun-ichi
J
University of Tokyo, Graduate School of Medicine, Department of Advanced Clinical Science and Therapeutics, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. junichisuzuki-circ@umin.ac.jp
Ogawa
Masahito
M
Muto
Susumu
S
Itai
Akiko
A
Isobe
Mitsuaki
M
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D010550:Personal Space; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D045162:Thiazolidinediones / Q000627:therapeutic use*
C530962:3-(3,4-dichlorobenzyl)-5-(3,4,5-trihydroxybenzylidene)thiazolidine-2,4-dione; D016207:Cytokines; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D045162:Thiazolidinediones