P2X7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharide-induced vascular dysfunction

Pro-inflammatory cytokines, chemokines and the reactive oxygen species are excessively produced in endotoxemia. However, attempting to inhibit all of these inflammatory signaling pathways at the same time in order to prevent endotoxemia is difficult. In a previous study we observed that activation of P2X7 receptors elicited the release of interleukin (IL)-1β from lipopolysaccharide (LPS)-incubated vessels. In the present study we hypothesize that P2X7 receptor activation is the initial event leading to vascular dysfunction following LPS treatment. LPS-induced decreases in mean arterial blood pressure and pressor responses to norepinephrine were attenuated in P2X7 knockout (P2X7KO) mice. Hypo-reactivity to phenylephrine in isolated mesenteric arteries by LPS treatment was also observed in C57BL/6 (wild type, WT) mice, which was prevented by IL-1 receptor antagonist (IL1ra), L-NAME and indomethacin, and in P2X7KO mice. Additionally, treatment with IL1ra plus L-NAME produced an additive inhibition of LPS-induced vascular hypo-reactivity, suggesting different signaling pathways between IL-1β and nitric oxide synthase (NOS). LPS-induced plasma levels of IL-1β, tumor necrosis factor (TNF)-α, IL-10, vascular eNOS and cyclooxygenase (COX)2 protein expression, as determined by ELISA and western blot, observed in WT mice were inhibited by IL1ra and in P2X7KO mice. These results suggest that P2X7 receptor activation involves an initial upstream mechanism of L...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research