In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 16 ( 2018-10-16), p. 1706-1719
Abstract:
The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X, is expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. Methods: We generated apolipoprotein E-deficient ( ApoE -/- ) mice lacking systemic PAR-2 expression ( PAR-2 -/- ApoE -/- ). ApoE -/- mice, which lack or express PAR-2 only in bone marrow (BM) cells, were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a Western-type diet by histological analyses, quantitative reverse transcription polymerase chain reaction, and Western blotting. In vitro experiments using BM-derived macrophages were performed to confirm the proinflammatory roles of PAR-2. The association between plasma activated factor X level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. Results: PAR-2 -/- ApoE -/- mice showed reduced atherosclerotic lesions in the aortic arch ( P 〈 0.05) along with features of stabilized atherosclerotic plaques, such as less lipid deposition ( P 〈 0.05), collagen loss ( P 〈 0.01), macrophage accumulation ( P 〈 0.05), and inflammatory molecule expression ( P 〈 0.05) compared with ApoE -/- mice. Systemic PAR2 deletion in ApoE -/- mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE -/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that activated factor X or a specific peptide agonist of PAR-2 significantly increased the expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2–deficient mice. Activation of nuclear factor-κB signaling was involved in PAR-2–associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma activated factor X level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score ( P 〈 0.05) and plaque volume ( P 〈 0.01). Conclusions: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE -/- mice. This signaling pathway may also participate in atherogenesis in humans.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/CIRCULATIONAHA.118.033544
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2018
detail.hit.zdb_id:
1466401-X
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