Published online before print August 30, 2004, doi: 10.1161/01.CIR.0000141803.41217.B6
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(Circulation. 2004;110:1276-1283.)
© 2004 American Heart Association, Inc.
Original Articles |
Thioredoxin-1 Ameliorates Myosin-Induced Autoimmune Myocarditis by Suppressing Chemokine Expressions and Leukocyte Chemotaxis in Mice
From the Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto (W.L., M.T., S.O., M.K.A., A.S., J.Y.); Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto (H.N.); Research Unit for Clinical Allergy, RIKEN Research Center for Allergy and Immunology, Yokohama (Y.I.); and Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto (K.S., C.K.), Japan.
Correspondence to Hajime Nakamura, MD, PhD, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail hnakamur{at}kuhp.kyoto-u.ac.jp
Received April 12, 2004; revision received June 24, 2004; accepted July 6, 2004.
Background— Cardiac myosin–induced myocarditis is an experimental autoimmune myocarditis (EAM) model used to investigate autoimmunological mechanisms in inflammatory heart diseases and resembles fulminant myocarditis in humans. We investigated the therapeutic role of thioredoxin-1 (TRX-1), a redox-regulatory protein with antioxidant and antiinflammatory effects, in murine EAM.
Methods and Results— EAM was generated in 5-week-old male BALB/c mice by immunization with porcine cardiac myosin at days 0 and 7. Recombinant human TRX-1 (rhTRX-1), C32S/C35S mutant rhTRX-1, or saline was administered intraperitoneally every second day from day 0 to 20. In addition, rabbit anti-mouse TRX-1 serum or normal rabbit serum was administered intraperitoneally on days –1, 2, and 6. Animals were euthanized on day 21. Histological analysis of the heart showed that TRX-1 significantly reduced the severity of EAM, whereas mutant TRX-1 failed to have such an effect, and anti–TRX-1 antibody enhanced the disease markedly. Immunohistochemical analysis showed that TRX-1 significantly suppressed cardiac macrophage inflammatory protein (MIP)-1
, MIP-2, and 8-hydroxydeoxyguanosine expression and macrophage infiltration into the heart in EAM. Although serum levels of MIP-1 were not suppressed by TRX-1 until day 21, both an in vitro chemotaxis chamber assay and an in vivo air pouch model showed that TRX-1 significantly suppressed MIP-1– or MIP-2–induced leukocyte chemotaxis. However, real-time reverse transcription–polymerase chain reaction showed that TRX-1 failed to decrease chemokine receptor expression increased in the bone marrow cells of EAM mice.
Conclusions— TRX-1 attenuates EAM by suppressing chemokine expressions and leukocyte chemotaxis in mice.
Key Words: thioredoxin • myosin • myocarditis
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