title: Cytokine gene therapy for myocarditis by in vivo electroporation.
abstract: Cytokines are important pathophysiologic and pathogenic factors in cardiovascular disorders, including viral myocarditis. We attempted to treat viral myocarditis with cytokine gene therapy by transferring an inhibitory cytokine, IL-1 receptor antagonist (IL-1ra) or viral IL-10 (vIL-10), by in vivo electroporation, a new method for gene transfer into muscle. Four-week-old male DBA/2 mice were inoculated intraperitoneally with 10 PFU of encephalomyocarditis virus. Immediately after virus inoculation, an expression plasmid carrying IL-1ra or vIL-10 was injected into tibialis anterior muscles followed by electroporation. Serum levels of IL1ra and vIL-10 reached 10.5 and 2.3 ng/ml, respectively, on day 5, when gene expression reached its peak. Histopathological examination showed that myocardial cellular infiltration was improved in mice treated with IL-1ra or vIL-10 compared with the control group. On day 14 after the onset of myocarditis, transfer of IL1ra or vIL-10 expression plasmid had significantly improved the survival rates of the animals. The expression of TNF-alpha was decreased to 0.60-fold (p < 0.005) and inducible nitric oxide synthase (iNOS) 0.43-fold (p < 0.005) by IL-1ra treatment, and the expression of IFN-gamma in the heart was decreased to 0.35-fold (p < 0.05), and iNOS 0.21-fold (p < 0.005), by vIL-10 relative to the controls. These results show that gene therapy with IL-1ra or vIL-10 expression plasmid was effective in the treatment of viral myocarditis, and in vivo electroporation may be a useful method by which to deliver cytokine therapy in cardiovascular diseases.
authors: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8357, Japan.
authors: A
authors: A
authors: Nakano
authors: A
authors: A
authors: Matsumori
authors: S
authors: S
authors: Kawamoto
authors: H
authors: H
authors: Tahara
authors: E
authors: E
authors: Yamato
authors: S
authors: S
authors: Sasayama
authors: J I
authors: JI
authors: Miyazaki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics*; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation / Q000379:methods*; D004686:Encephalomyocarditis virus / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009132:Muscles / Q000378:metabolism; D009205:Myocarditis / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat