Abstract 1591: Central Gene Transfer of Interleukin-10 Reduces Hypothalamic Expression of Inflammatory Mediators and Sympathetic Drive in Rats After Myocardial Infarction
Introduction: The increased expression of pro-inflammatory cytokines (PIC) in the hypothalamus of rats with heart failure following myocardial infarction (MI) may activate the sympathetic nervous system and facilitate volume accumulation. Interleukin (IL)-10 is a potent anti-inflammatory cytokine that modulates the inflammatory response.
Hypothesis: Central gene transfer of IL-10 will modulate or prevent the increase in pro-inflammatory cytokines in brain tissues and ameliorate the augmented sympathetic drive in rats after MI.
Methods: Sprague Dawley rats underwent coronary ligation to induce MI (n=21) or sham surgery (SHAM, n=20), confirmed by echocardiography. Seven days after MI, adenoviral vectors encoding human IL-10 (ADIL10) or β-galactosidase (βGal, control) were injected (30 μL over 30 min) into lateral ventricle.
Results: Two weeks after MI, abundant expression of ADIL10 mRNA was detected by RT-PCR in the hypothalamus of ADIL10-treated MI (n=11) and SHAM (n=10) rats but not in βGal-treated MI (n=10) or SHAM (n=10) rats. Compared with βGal-treated SHAM, βGal-treated MI rats had increased (*P<0.05) hypothalamic IL-1β (0.36±0.07* vs 0.07±0.02), tumor necrosis factor-α (TNF-α, 0.37±0.04* vs 0.12±0.02) and cyclooxygenase-2 (COX-2, 0.16±0.03* vs 0.06±0.01) mRNA by real-time PCR (normalized to GAPDH). βGal-treated MI rats also showed higher cerebrospinal fluid prostaglandin E2 (CSF PGE2,1125±152* vs 397±45 pg/ml) and plasma norepinephrine (NE, 1160±167* vs 252±48 pg/ml) by ELISA, and more Fra-LI-positive neurons (66±6* vs 26±5) in paraventricular nucleus (PVN) of hypothalamus by immunohistochemistry. Compared with βGal-treated MI, ADIL10-treated MI rats had lower (#P<0.05) IL-1β (by 51%#) and COX-2 (by 42%#) but not TNF-α mRNA in hypothalamus, lower CSF PGE2 (by 36%#) and plasma NE (by 43%#) and less Fra-LI-positive neurons (by 35%#) in the PVN. No effects were found in ADIL10-treated SHAM.
Conclusion: Central gene transfer of the anti-inflammatory cytokine IL-10 attenuates the expression of inflammatory/excitatory mediators in hypothalamus and reduces sympathetic nerve activity in MI rats. Upregulation of anti-inflammatory cytokines in the brain may be a novel approach to treatment of sympathetic excitation after MI.