Erythropoietin attenuates the development of experimental autoimmune myocarditis.
OBJECTIVE
Erythropoietin (EPO) has been shown to not only have cardioprotective effects but also attenuate autoimmune diseases. In the present study, we investigated the effect of EPO on cardiac inflammation and function, inflammatory cell infiltration, and cytokine expression in a rat model of experimental autoimmune myocarditis (EAM).


RESULTS
Male Lewis rats (6-8 weeks old) were immunized on day 0 with porcine cardiac myosin to establish EAM. The rats were subcutaneously administered either vehicle (saline) or human recombinant EPO (6,000 U/kg, 3 days/week) from day 0 to 20, and they were evaluated on day 21. In the EPO group, the inflammation area and heart weight/body weight ratio were significantly attenuated as compared with those in the vehicle group. Blood pressure and cardiac function were also improved in the EPO group. Immunohistochemistry revealed that EPO decreased the infiltration of macrophages and CD4 T cells, and degranulated mast cells in the myocardium. Real-time RT-PCR analysis demonstrated that inflammatory cytokine expression in the myocardium and lymphocytes was suppressed in the EPO group. However, in vitro experiments showed that EPO had no effect on antigen-induced proliferation and cytokine expression in lymphocytes.


CONCLUSIONS
EPO attenuates inflammatory cell infiltration and cytokine expression, and it improves cardiac function and reduces cardiac inflammation in EAM. This beneficial effect of EPO is unlikely to arise from a direct anti-inflammatory action on lymphocytes. These findings suggest the therapeutic potential of EPO for the treatment of myocarditis.
Hirose
Sho-Ichi
S
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
Ogawa
Ryo
R
Morimoto
Hajime
H
Izawa
Atsushi
A
Sato
Hajime
H
Ise
Hirohiko
H
Hongo
Minoru
M
Ikeda
Uichi
U
D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000008:administration & dosage / Q000633:toxicity; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000145:classification / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D006454:Hemoglobins / Q000378:metabolism; D007120:Immunochemistry; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D024722:Cardiac Myosins