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

ABSTRACT: 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)?1? 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. CXCR7 is upregulated in human carotid plaque tissues, HFD?treated ApoE?/? mouse aortas, and ox?LDL?treated HUVECs. Activation of CXCR7 alleviates ox?LDL?induced endothelial injury and cell pyroptosis. Activation of CXCR7 reduces atherosclerosis progression by mitigating the pyroptosis pathway in vivo.

SUBMITTER: Qiu L

PROVIDER: S-EPMC7511884 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque. METHODS:One hundred and thirty-two symptomatic patients with ?2?mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors. RESULTS:A decreased vessel wall Ktrans was found for IPH positive patients (0.051?±?0.011?min-?1 versus 0.058?±?0.017?min-?1, p?=?0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057?±?0.012?min-?1 and 0.057?±?0.018?min-?1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n?=?8) and plaques with IPH (n?=?15) (0.000333?±?0.0000707 vs. and 0.000289?±?0.0000439, p?=?0.585). CONCLUSIONS:A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development. TRIAL REGISTRATION:NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).

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

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