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TMAO Activates Carotid Endothelial Inflammasomes Leading to Enhanced Neointimal Formation in Nlrp3 Mice
Author(s) -
Boini Krishna M.,
Puchchakayala Goverdhan,
Zhang Yang,
Koka Saisudha
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07299
Subject(s) - inflammasome , chemistry , knockout mouse , colocalization , inflammation , trimethylamine n oxide , medicine , endocrinology , microbiology and biotechnology , biochemistry , receptor , biology , trimethylamine
Recent studies have shown that gut microbial metabolite, trimethylamine‐N‐Oxide (TMAO), is a biomarker for atherosclerosis. However, the mechanisms of how TMAO induces atherosclerosis are still unclear. The present study tested whether TMAO induces Nlrp3 inflammasome activation and consequent endothelial injury leading to atherosclerotic lesion development in the carotid arterial wall. Confocal microscopy showed that colocalization of Nlrp3 with ASC significantly increased in the intima of the carotid arteries of TMAO‐treated Nlrp3 +/+ mice, suggesting the formation of Nlrp3 inflammasomes in the endothelium of these arteries. In Nlrp3 −/− mice, however, such colocalization was much less detected. In consistent with inflammasome formation, TMAO‐induced IL‐1β production in the intima was abolished in Nlrp3 −/− mice. Furthermore, we found that TMAO treatment decreased ZO2, VE‐cadherin and occuludin expression in carotid arteries of Nlrp3 +/+ mice but not in Nlrp3 −/− mice, signifying tight junction disruption in the carotid arteries of Nlrp3 +/+ mice. In addition, we found that TMAO treatment had significantly increased vascular permeability to intravenously injected Evans blue dye compared to vehicle treated Nlrp3 +/+ mice. However, such TMAO‐induced vascular permeability was attenuated in Nlrp3 −/− mice, suggesting that Nlrp3 inflammasome activation plays an important role in TMAO‐induced vascular leakage in mouse hearts. Furthermore, we also found that TMAO markedly increased neointimal formation in partially ligated left carotid arteries (PLCA) of Nlrp3 +/+ mice. However, such TMAO‐enhanced neointimal formation and increased I/M ratio in PLCA was markedly attenuated in Nlrp3 −/− mice. These results suggest that the formation and activation of NLRP3 inflammasomes by TMAO may be an important mechanism in initiating endothelial inflammatory response leading to arterial inflammation and endothelial dysfunction and consequent atherosclerosis in mice. Support or Funding Information R01DK104031 and R56HL143809