ID | 112891 |
Title Alternative | Roles of PAR-2 in atherogenesis
Roles of Protease-Activated Receptor-2 in Atherogenesis
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Author |
Hara, Tomoya
Tokushima University
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Phuong, Pham Tran
Tokushima University
Yamaguchi, Koji
Tokushima University
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Nishimoto, Sachiko
Tokushima University
Yagi, Shusuke
Tokushima University
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Kusunose, Kenya
Tokushima University
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Yamada, Hirotsugu
Tokushima University
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Soeki, Takeshi
Tokushima University
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Wakatsuki, Tetsuzo
Tokushima University
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Sata, Masataka
Tokushima University
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Keywords | macrophage
protease-activated receptor-2
atherosclerosis
inflammation
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Content Type |
Journal Article
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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
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ISSN | 00097322
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NCID | AA12326270
AA00133542
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Publisher | American Heart Association, Inc.
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Volume | 138
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Issue | 16
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Start Page | 1706
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End Page | 1719
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Published Date | 2018-04-26
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EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
FullText File | |
language |
eng
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TextVersion |
Author
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departments |
Medical Sciences
University Hospital
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