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
beta-galactosidase (betaGal) were injected (30 microL 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+betaGal, MI+betaGal had increased (P<0.05) IL-1beta and
cyclooxygenase-2 mRNA and
protein and
nuclear factor kappaB activity in the hypothalamus,
cyclooxygenase-2 fluorescence in perivascular cells of the paraventricular nucleus of hypothalamus,
prostaglandin E(2) 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-alpha and circulating
tumor necrosis factor-alpha and IL-1beta levels, also increased in MI+betaGal, 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.