Activation of CXCR7 promotes endothelial repair and reduces the carotid atherosclerotic lesions through inhibition of pyroptosis signaling pathways

Lisha Qiu, Min Zhang, Sheng Zhang, Yalin Tang, Yanyan Zhang, Congcong Li, Yi Wang, Li Jiang, Jialin C. Zheng

Research output: Contribution to journalArticle

Abstract

Endothelial injuries, including cell pyroptosis, are ongoing inflammatory processes with key roles in atherosclerosis development. Our previous report showed that the chemokine CXCL12 and its receptor CXCR7 are associated with the proliferation and angiogenesis of endothelial cells. Nevertheless, the mechanism underlying these effects on atherosclerotic lesions, especially on endothelial dysfunction, remains unknown. Here, we demonstrated that CXCR7 was upregulated in human carotid atherosclerotic plaques, apolipoprotein E knockout (ApoE−/−) mice fed with a high-fat diet (HFD), and oxidized lipopolysaccharide-treated (ox-LDL) human umbilical vein endothelial cells (HUVECs). Further, the activation of CXCR7 reversed ox-LDL-induced HUVEC dysfunction, such as migration, tube formation, and cell pyroptosis; all of these protective effects were alleviated by inhibition of CXCR7. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes were also elevated in human carotid atherosclerotic plaques, ApoE−/− mice fed with HFD, and ox-LDL-injured HUVECs by regulation of caspase-1 and interleukin (IL)-1β expression. The activation of CXCR7 by TC14012 led to a decrease in atherosclerotic lesions in ApoE−/− mice fed with HFD. TC14012 also inhibited the expression of the NLRP3 inflammasome signaling pathway in vivo. In conclusion, our study suggests that CXCR7 plays an important role in regulating NLRP3 inflammasome-modulated pyroptosis in HUVECs, providing a potential novel therapy for atherosclerosis.

Original languageEnglish (US)
JournalAging cell
DOIs
StateAccepted/In press - 2020

Keywords

  • CXCR7
  • NLRP3
  • atherosclerosis
  • human umbilical vein endothelial cells
  • ox-LDL

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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