Published online before print September 27, 2001, doi: 10.1161/hh2201.099373
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© 2001 American Heart Association, Inc.
Integrative Physiology |
cis Element Decoy Against Nuclear Factor-
B Attenuates Development of Experimental Autoimmune Myocarditis in Rats
From the Departments of Internal Medicine I (O.Y., J.S., H.K., N.W., M.I.) and Surgery II (Y.W.), Shinshu University School of Medicine, Nagano, Japan; the Division of Gene Therapy Science (M.A., R.M., Y.K.) and the Department of Geriatric Medicine (T.O.), Osaka University Graduate School of Medicine, Osaka, Japan; and the Department of Cardiovascular Medicine (H.F., Y.K., M.I.), Tokyo Medical and Dental University School of Medicine, Tokyo, Japan.
Correspondence to Mitsuaki Isobe, MD, Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp
Abstract—— Nuclear factor-
B (NFB) plays a significant role in the coordinated transactivation of cytokine, inducible NO synthase (iNOS), and adhesion molecule genes. Although inflammation is an essential pathological feature of myocarditis, the role of NFB in this process remains obscure. We examined the role of NFB in the progression of rat experimental autoimmune myocarditis (EAM) and tested the hypothesis that NFB blockade with a decoy against the cis element of NFB can prevent the progression of EAM. Lewis rats were immunized with purified porcine cardiac myosin to establish EAM on day 0. NFB decoy was infused into the rat coronary artery on day 0 (group NF0), 7 (group NF7), or 14 (group NF14) and harvested on day 21. Scrambled decoy was infused on day 0 (group SD0), 7 (group SD7), or 14 (group SD14) and served for control groups. The ratios of myocarditis-affected areas to the ventricular cross-sectional area of all treatment groups were significantly lower than those of the control groups (group NF0, 33±18% versus SD0, 53±14%; group NF7, 19±15% versus SD7, 50±16%; and group NF14, 34±10% versus SD14, 52±14%). Immunohistochemical and immunoblot analyses showed expression of ICAM-1, iNOS, IL-2, and TNF
in myocardium of scrambled decoy groups, and this expression was effectively suppressed by NFB decoy treatment. Thus, we found that NFB is a key regulator in the progression of EAM and that in vivo transfection of NFB decoy reduces the severity of EAM.
Key Words: myocarditis • gene therapy • nuclear factor-B
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