Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E–Deficient Mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-10, Vol.138 (16), p.1706-1719
• Main Authors: Hara, Tomoya, Phuong, Pham Tran, Fukuda, Daiju, Yamaguchi, Koji, Murata, Chie, Nishimoto, Sachiko, Yagi, Shusuke, Kusunose, Kenya, Yamada, Hirotsugu, Soeki, Takeshi, Wakatsuki, Tetsuzo, Imoto, Issei, Shimabukuro, Michio, Sata, Masataka
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.118.033544

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, 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-2ApoE). 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-2ApoE mice showed reduced atherosclerotic lesions in the aortic arch (P