著作: Hara Tomoya/Phuong Tran Pham/[福田 大受]/[山口 浩司]/Murata Chie/Nishimoto Sachiko/[八木 秀介]/[楠瀬 賢也]/[山田 博胤]/Takeshi Soeki/[若槻 哲三]/Imoto Issei/[島袋 充生]/[佐田 政隆]/Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice./[Circulation]
(英) Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.
(英) -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. -We generated apolipoprotein E-deficient ( ) mice lacking systemic PAR-2 expression ( ). 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. - mice showed reduced atherosclerotic lesions in the aortic arch (<0.05) along with features of stabilized atherosclerotic plaques such as less lipid deposition (<0.05), collagen loss (<0.01), macrophage accumulation (<0.05), and inflammatory molecule expression (<0.05) compared with mice. Systemic PAR2 deletion in 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 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 (<0.05) and plaque volume (<0.01). -PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in mice. This signaling pathway may also participate in atherogenesis in humans.
Circulation([American Heart Association])
|年月日||必須||2018年 4月 26日|