Endothelial NLRP3 inflammasome activation and enhanced neointima formation in mice by adipokine visfatin

Min Xia, Krishna M. Boini, Justine M. Abais, Ming Xu, Yang Zhang, Pin Lan Li

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Inflammasomes serve as an intracellular machinery to initiate inflammatory response to various danger signals. The present study tested whether an inflammasome centered on nucleotide oligomerization domain-like receptor protein 3 (NLRP3) triggers endothelial inflammatory response to adipokine visfatin, a major injurious adipokine during obesity. NLRP3 inflammasome components were abundantly expressed in cultured mouse microvascular endothelial cells, including NLRP3, apoptosis-associated speck-like protein, and caspase-1. These NLRP3 inflammasome molecules could be aggregated to form an inflammasome complex on stimulation of visfatin, as shown by fluorescence confocal microscopy and size exclusion chromatography. Correspondingly, visfatin significantly increased caspase-1 activity and IL-1β release in microvascular endothelial cells, indicating an activation of NLRP3 inflammasomes. In animal experiments, direct infusion of visfatin in mice with partially ligated left carotid artery were found to have significantly increased neointimal formation, which was correlated with increased NLRP3 inflammasome formation and IL-1β production in the intima. Further, visfatin-induced neointimal formation, endothelial inflammasome formation, and IL-1β production in mouse partially ligated left carotid artery were abolished by caspase-1 inhibition, local delivery of apoptosis-associated speck-like protein shRNA or deletion of the ASC gene. In conclusion, the formation and activation of NLRP3 inflammasomes by adipokine visfatin may be an important initiating mechanism to turn on the endothelial inflammatory response leading to arterial inflammation and endothelial dysfunction in mice during early stage obesity.

Original languageEnglish (US)
Pages (from-to)1617-1628
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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