ID 112891
Title Alternative
Roles of PAR-2 in atherogenesis
Roles of Protease-Activated Receptor-2 in Atherogenesis
Author
Hara, Tomoya Tokushima University
Phuong, Pham Tran Tokushima University
Nishimoto, Sachiko Tokushima University
Keywords
macrophage
protease-activated receptor-2
atherosclerosis
inflammation
Content Type
Journal Article
Description
Background: 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 (FXa), are 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 (WTD) by histological analyses, quantitative RT-PCR, and western blotting. In vitro experiments using BM-derived macrophages were performed to confirm pro-inflammatory roles of PAR-2. The association between plasma FXa 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 FXa or a specific peptide agonist of PAR-2 significantly increased 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 NF-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma FXa 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.
Journal Title
Circulation
ISSN
00097322
NCID
AA12326270
AA00133542
Publisher
American Heart Association, Inc.
Volume
138
Issue
16
Start Page
1706
End Page
1719
Published Date
2018-04-26
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Author
departments
Medical Sciences
University Hospital