P2X 7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharideinduced vascular dysfunction

Chin Wei Chiao, J. Eduardo da Silva-santos, Fernanda R. Giachini, Rita C. Tostes, Ming Jai Su, R Clinton Webb

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Pro-inflammatory cytokines, chemokines and ROS (reactive oxygen species) are excessively produced in endotoxaemia. However, attempting to inhibit all of these inflammatory signalling pathways at the same time in order to prevent endotoxaemia is difficult. In a previous study we observed that activation of P2X 7 receptors elicited the release of IL (interleukin)-1β from LPS (lipopolysaccharide)-incubated vessels. In the present study, we hypothesize that P2X 7 receptor activation is the initial event leading to vascular dysfunction following LPS treatment. LPS-induced decreases in MAP (mean arterial pressure) and pressor responses to NE (noradrenaline) were attenuated in P2X 7 KO (P2X 7 -knockout) mice. Hyporeactivity in response to PE (phenylephrine) in isolated mesenteric arteries by LPS treatment was also observed in C57BL/6 [WT (wild-type)] mice, which was prevented by IL1ra (IL-1 receptor antagonist), L-NAME (N G -nitro-L-arginine methyl ester) and indomethacin and in P2X 7 KO mice. In addition, treatment with IL1ra plus L-NAME produced an additive inhibition of LPS-induced vascular hyporeactivity, suggesting different signalling pathways between IL-1β and NOS (NO synthase). LPS-induced plasma levels of IL-1β, TNFα (tumour necrosis factor α), IL-10, vascular eNOS (endothelial NOS) and COX2 (cyclo-oxygenase 2) protein expression, as determined by ELISA and Western blot, observed in WT mice were inhibited by IL1ra and in P2X 7 KO mice. These results suggest that P2X 7 receptor activation involves an initial upstream mechanism of LPS-induced vascular dysfunction, which is associated with IL-1β-mediated eNOS, COX2 activation and TNFα release.

Original languageEnglish (US)
Pages (from-to)131-141
Number of pages11
JournalClinical Science
Volume125
Issue number3
DOIs
StatePublished - Aug 1 2013

Fingerprint

Blood Vessels
Lipopolysaccharides
Interleukin-1
Interleukin-1 Receptors
NG-Nitroarginine Methyl Ester
Knockout Mice
Endotoxemia
Prostaglandin-Endoperoxide Synthases
Nitric Oxide Synthase
Tumor Necrosis Factor-alpha
Mesenteric Arteries
Phenylephrine
Chemokines
Indomethacin
Interleukin-10
Reactive Oxygen Species
Norepinephrine
Arterial Pressure
Therapeutics
Western Blotting

Keywords

  • Cyclo-oxygenase
  • Interleukin-1β
  • Nitric oxide synthase
  • P2X receptor
  • Sepsis
  • Tumour necrosis factor
  • lipopolysaccharide

ASJC Scopus subject areas

  • Medicine(all)

Cite this

P2X 7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharideinduced vascular dysfunction . / Chiao, Chin Wei; da Silva-santos, J. Eduardo; Giachini, Fernanda R.; Tostes, Rita C.; Su, Ming Jai; Webb, R Clinton.

In: Clinical Science, Vol. 125, No. 3, 01.08.2013, p. 131-141.

Research output: Contribution to journalArticle

Chiao, Chin Wei ; da Silva-santos, J. Eduardo ; Giachini, Fernanda R. ; Tostes, Rita C. ; Su, Ming Jai ; Webb, R Clinton. / P2X 7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharideinduced vascular dysfunction In: Clinical Science. 2013 ; Vol. 125, No. 3. pp. 131-141.
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AU - Tostes, Rita C.

AU - Su, Ming Jai

AU - Webb, R Clinton

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