Central gene transfer of interleukin-10 reduces hypothalamic inflammation and evidence of heart failure in rats after myocardial infarction.

Abstract

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.

• Authors: Yang Yu, Zhi-Hua Zhang, Shun-Guang Wei, Yi Chu, Robert M Weiss, Donald D Heistad, Robert B Felder
• Journal: Circulation research (Circ Res) Vol. 101 Issue 3 Pg. 304-12 (Aug 03 2007) ISSN: 1524-4571 [Electronic] United States
• PMID: 17569888 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• IL10 protein, human
• Interleukin-1beta
• NF-kappa B
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Dinoprostone
• Norepinephrine

Topics

• Adenoviridae (genetics)
• Animals
• Brain
• Cyclooxygenase 2 (biosynthesis, genetics)
• Cytokines (biosynthesis, genetics)
• Dinoprostone (biosynthesis, cerebrospinal fluid)
• Disease Progression
• Gene Transfer Techniques
• Genetic Vectors (administration & dosage, therapeutic use)
• Heart Failure (diagnostic imaging, etiology, physiopathology, prevention & control)
• Heart Ventricles (pathology)
• Injections
• Interleukin-10 (genetics, physiology)
• Interleukin-1beta (biosynthesis, genetics)
• Ligation
• Lung (pathology)
• Male
• Myocardial Infarction (complications)
• NF-kappa B (metabolism)
• Norepinephrine (blood)
• Organ Size
• Paraventricular Hypothalamic Nucleus (metabolism, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (genetics, physiology)
• Sympathetic Nervous System (physiopathology)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)
• Ultrasonography
• Ventricular Remodeling