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(Circulation Research. 2007;101:304.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Central Gene Transfer of Interleukin-10 Reduces Hypothalamic Inflammation and Evidence of Heart Failure in Rats After Myocardial Infarction

Yang Yu, Zhi-Hua Zhang, Shun-Guang Wei, Yi Chu, Robert M. Weiss, Donald D. Heistad, Robert B. Felder

From the Department of Internal Medicine (Y.Y., Z.-H.Z., S.-G.W., Y.C., R.M.W., D.D.H., R.B.F.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa; and Veterans Affairs Medical Center (R.M.W., D.D.H., R.B.F.), Iowa City.

Correspondence to Robert B. Felder, MD, University of Iowa College of Medicine, E318-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-felder{at}uiowa.edu

The expression of proinflammatory cytokines increases in hypothalamus of rats with myocardial infarction (MI) and heart failure. We used central gene transfer of human interleukin (IL)-10, a potent antiinflammatory cytokine, to counter the effects of brain proinflammatory cytokines and examine their functional significance. Sprague–Dawley rats underwent coronary ligation to induce MI or sham surgery (SHAM). One week later, adenoviral vectors encoding human IL-10 (AdIL-10) or ß-galactosidase (ßGal) were injected (30 µL over 30 minutes) into lateral ventricle. One week after injection, there was abundant expression of human IL-10 in the brain of MI+AdIL-10 and SHAM+AdIL-10 rats. Compared with SHAM+ßGal, MI+ßGal had increased (P<0.05) IL-1ß and cyclooxygenase-2 mRNA and protein and nuclear factor B activity in the hypothalamus, cyclooxygenase-2 fluorescence in perivascular cells of the paraventricular nucleus of hypothalamus, prostaglandin E₂ in cerebrospinal fluid, and Fra-like activity (indicating neuronal excitation) in paraventricular nucleus. Plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased and maximal left ventricular dP/dt was decreased. All of these findings were ameliorated in MI rats treated with AdIL-10. Hypothalamic tumor necrosis factor- and circulating tumor necrosis factor- and IL-1ß levels, also increased in MI+ßGal, were not affected by AdIL-10 treatment. Rat native IL-10 was not affected by MI or AdIL-10. AdIL-10 had no effects on SHAM rats. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after MI can be modulated by manipulating the balance between proinflammatory and antiinflammatory cytokines in the brain.

Key Words: brain • proinflammatory cytokines • adenoviral vector • autonomic regulation

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