ID 112891
タイトル別表記
Roles of PAR-2 in atherogenesis
Roles of Protease-Activated Receptor-2 in Atherogenesis
著者
Hara, Tomoya Tokushima University
Phuong, Pham Tran Tokushima University
Nishimoto, Sachiko Tokushima University
キーワード
macrophage
protease-activated receptor-2
atherosclerosis
inflammation
資料タイプ
学術雑誌論文
抄録
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.
掲載誌名
Circulation
ISSN
00097322
cat書誌ID
AA12326270
AA00133542
出版者
American Heart Association, Inc.
138
16
開始ページ
1706
終了ページ
1719
発行日
2018-04-26
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
著者版
部局
医学系
病院