Abstract P2011: Chronic Systemic Administration of Pro-Inflammatory Cytokines Causes Cardiovascular Dysfunction and Downregulates Brain Expression of Regulator of G-Protein Signaling-10 in Rats

Abstract

Systemic pro-inflammatory cytokines (PICs) promote central oxidative stress and neuroinflammation that contribute to sympathetic excitation and cardiovascular dysfunction in hypertension and heart failure. However, the key molecular regulators of neuroinflammatory responses in the brain remain unclear. Regulator of G-protein Signaling-10 (RGS10), a GTPase-accelerating protein that is expressed predominantly in the brain, has recently emerged as an important counter regulator of PICs-induced downstream signaling in the central nervous system. RGS10 negatively regulates NF-kB-mediated inflammatory responses in microglia and antagonizes neurotoxic effects of peripheral inflammation. The present study examined whether peripherally administered PICs alter RGS10 expression in cardiovascular/autonomic brain regions like subfornical organ (SFO) and hypothalamic paraventricular nucleus (PVN). Male SD rats received a 2-week subcutaneous infusion of vehicle, interleukin (IL)-1β (400 ng/day) and tumor necrosis factor (TNF)-α (600 ng/day). Rats treated with IL-1β (n=6) or TNF-α (n=6) had significantly (*P<0.05) reduced mRNA level (fold change) of RGS10 in SFO (0.60±0.15* or 0.69±0.16* vs 1.03±0.28; IL-1β or TNF-α, vs vehicle treatment) and PVN (0.72±0.15* or 0.71±0.19* vs 1.02±0.24), and lessoned mRNA level of NF-kB inhibitor IkB-α (SFO: 0.60±0.21* or 0.55±0.16* vs 1.07±0.46; PVN: 0.70±0.31* or 0.82±0.16* vs 1.00±0.07). Treatments with IL-1β or TNF-α increased mRNA level of NADPH oxidase 2 (SFO: 1.96±0.91* or 1.62±0.47* vs 1.03±0.28; PVN: 2.00±0.82* or 1.74±0.70* vs 1.00±0.15) and cyclooxygenase-2 (SFO: 1.78±0.76* or 1.98±1.04* vs 1.00±0.13; PVN: 1.68±0.34* or 1.62±0.57* vs 1.02±0.24). Rats treated with IL-1β or TNF-α had elevated mean blood pressure (98±11* or 100±9* vs 84±5 mmHg) and increased sympathetic activity as indicated by pressure response to ganglionic blockade (38±7 * or 36±6* vs 28±4 mmHg). Additionally, IL-1β or TNF-α-treated rats had increased cardiac fibrotic markers and impaired cardiac diastolic function. These results suggest that circulating PICs reduce RGS10 expression in the brain, which may contribute to sympathetic excitation and cardiovascular dysfunction in inflammatory conditions.