cis Element decoy against nuclear factor-kappaB attenuates development of experimental autoimmune myocarditis in rats.

Abstract

Nuclear factor-kappaB (NFkappaB) 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 NFkappaB in this process remains obscure. We examined the role of NFkappaB in the progression of rat experimental autoimmune myocarditis (EAM) and tested the hypothesis that NFkappaB blockade with a decoy against the cis element of NFkappaB can prevent the progression of EAM. Lewis rats were immunized with purified porcine cardiac myosin to establish EAM on day 0. NFkappaB 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 TNFalpha in myocardium of scrambled decoy groups, and this expression was effectively suppressed by NFkappaB decoy treatment. Thus, we found that NFkappaB is a key regulator in the progression of EAM and that in vivo transfection of NFkappaB decoy reduces the severity of EAM.

• Authors: O Yokoseki, J Suzuki, H Kitabayashi, N Watanabe, Y Wada, M Aoki, R Morishita, Y Kaneda, T Ogihara, H Futamatsu, Y Kobayashi, M Isobe
• Journal: Circulation research (Circ Res) Vol. 89 Issue 10 Pg. 899-906 (Nov 09 2001) ISSN: 1524-4571 [Electronic] United States
• PMID: 11701617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-2
• Liposomes
• NF-kappa B
• Oligonucleotides
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Cardiac Myosins

Topics

• Animals
• Autoimmune Diseases (complications, drug therapy, pathology, physiopathology)
• Cardiac Myosins (immunology)
• Disease Models, Animal
• Disease Progression
• Gene Expression (drug effects)
• Genetic Therapy (methods)
• Immunohistochemistry
• Infusions, Intra-Arterial
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Interleukin-2 (genetics, metabolism)
• Liposomes
• Male
• Myocarditis (complications, drug therapy, pathology, physiopathology)
• Myocardium (metabolism, pathology)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Nitric Oxide Synthase (genetics, metabolism)
• Nitric Oxide Synthase Type II
• Oligonucleotides (administration & dosage)
• Promoter Regions, Genetic (drug effects)
• Rats
• Rats, Inbred Lew
• T-Lymphocytes (immunology)
• Transcriptional Activation (drug effects)
• Tumor Necrosis Factor-alpha (genetics, metabolism)