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(Circulation. 2005;111:1593-1600.)
© 2005 American Heart Association, Inc.

Heart Failure

Effect of Hydrodynamics-Based Gene Delivery of Plasmid DNA Encoding Interleukin-1 Receptor Antagonist-Ig for Treatment of Rat Autoimmune Myocarditis

Possible Mechanism for Lymphocytes and Noncardiac Cells

Hui Liu, MD; Haruo Hanawa, MD; Tsuyoshi Yoshida, MD; Raafat Elnaggar, MD; Manabu Hayashi, MD; Ritsuo Watanabe, MD; Ken Toba, MD; Kaori Yoshida, BS; He Chang, MD; Yuji Okura, MD; Kiminori Kato, MD; Makoto Kodama, MD; Hiroki Maruyama, MD; Junichi Miyazaki, MD; Mikio Nakazawa, PhD; Yoshifusa Aizawa, MD

From the Divisions of Cardiology (H.L., H.H., T.Y., R.E., M.H., R.W., K.T., K.Y., H.C., Y.O., K.K., M.K., Y.A.) and Clinical Nephrology and Rheumatology (H.M.), Niigata University Graduate School of Medical and Dental Sciences, and Department of Medical Technology, School of Health Sciences, Faculty of Medicine (M.N.), Niigata University, Niigata, and Division of Stem Cell Regulation Research, Osaka University Medical School (J.M.), Suita, Japan.

Correspondence to H. Hanawa, Division of Cardiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8120, Japan. E-mail hanawa{at}med.niigata-u.ac.jp

Received May 26, 2004; revision received November 5, 2004; accepted November 10, 2004.

Background— Interleukin-1 (IL-1) is a powerful and important cytokine in myocarditis. The purpose of this study was to evaluate the effect and possible mechanism of hydrodynamics-based delivery of the IL-1 receptor antagonist (IL-1RA)-immunoglobulin (Ig) gene for treatment of rat experimental autoimmune myocarditis (EAM).

Methods and Results— On the day after immunization, rats were transfected with either pCAGGS encoding IL-1RA-Ig or pCAGGS encoding Ig alone. On day 17, IL-1RA-Ig gene therapy was effective in controlling EAM, as monitored by a decreased ratio of heart weight to body weight, reduced myocarditis areas, reduced gene expression of atrial natriuretic peptide in hearts, and improved cardiac function in echocardiographic and hemodynamic parameters. Examination of the expression of IL-1–related genes in purified cells from EAM hearts suggested that ectopic IL-1RA-Ig-acting target cells were ßT cells and noncardiomyocytic noninflammatory cells such as fibroblasts, smooth muscle cells, and endothelial cells. Therefore, we examined the effect of serum containing IL-1RA-Ig on the expression of immune-relevant genes within noncardiomyocytic cells cultured from EAM hearts or concanavalin A-stimulated lymphocytes derived from lymph nodes in EAM-affected rats. The expression of immunologic molecules (prostaglandin E synthase, cyclooxygenase-2, and IL-1ß) in cultivated noncardiomyocytic cells and Th1 cytokines (IL-2 and IFN-) in lymphocytes was significantly decreased by the serum containing IL-1RA-Ig.

Conclusions— EAM was suppressed by hydrodynamics-based delivery of plasmid DNA encoding IL-1RA-Ig. In addition, IL-1RA-Ig suppressed gene expression of prostaglandin synthases and IL-1 in noncardiomyocytic cells and Th1 cytokines in lymphocytes.

Key Words: cardiomyopathy, dilated • cytokines • sialoglycoproteins • myocarditis • prostaglandins

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