P2X7 receptor activation amplifies lipopolysaccharide-induced vascular hyporeactivity via interleukin-1β release

Chin Wei Chiao, Rita C. Tostes, R. Clinton Webb

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Lipopolysaccharide (LPS) stimulates cytoplasmic accumulation of pro-interleukin (IL)-1β. Activation of P2X7 receptors stimulates conversion of pro-IL-1β into mature IL-1β, which is then secreted. Because both LPS (in vivo) and IL-1β (in vitro) decrease vascular reactivity to contractile agents, we hypothesized the following: 1) P2X 7 receptor activation contributes to LPS-induced vascular hyporeactivity, and 2) IL-1β mediates this change. Thoracic aortas were obtained from 12-week-old male C57BL/6 mice. The aortic rings were incubated for 24 h in Dulbecco's modified Eagle's medium, LPS, benzoylbenzoyl-ATP (BzATP; P2X7 receptor agonist), LPS plus BzATP, oxidized ATP (oATP; P2X 7 receptor antagonist), or oATP plus LPS plus BzATP. After the treatment, the rings were either mounted in a myograph for evaluation of contractile activity or homogenized for IL-1β and inducible nitric-oxide synthase (iNOS) protein measurement. In endothelium-intact aortic rings, phenylephrine (PE)-induced contractions were not altered by incubation with LPS or BzATP, but they significantly decreased in aortic rings incubated with LPS plus BzATP. Treatment with oATP or IL-1ra (IL-1β receptor antagonist) reversed LPS plus BzATP-induced hyporeactivity to PE. In the presence of N G-nitro-L-arginine methyl ester or N-([3-(aminomethyl)phenyl]methyl) ethanimidamide (selective iNOS inhibitor), the vascular hyporeactivity induced by LPS plus BzATP on PE responses was not observed. BzATP augmented LPS-induced IL-1β release and iNOS protein expression, and these effects were also inhibited by oATP. Moreover, incubation of endothelium-intact aortic rings with IL-1β induced iNOS protein expression. Thus, activation of P2X7 receptor amplifies LPS-induced hyporeactivity in mouse endothelium-intact aorta, which is associated with IL-1β-mediated release of nitric oxide by iNOS.

Original languageEnglish (US)
Pages (from-to)864-870
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume326
Issue number3
DOIs
StatePublished - Sep 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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