徳島大学 教育・研究者情報データベース(EDB)

1. (英) Hara Tomoya

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2. (英) Phuong Tran Pham

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3. 福田 大受

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4. 山口 浩司([徳島大学.病院.先端医科医療開発研究プロジェクト]/[徳島大学.病院.診療科.内科.循環器内科])

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5. (英) Murata Chie

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6. (英) Nishimoto Sachiko

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7. 八木 秀介([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.地域・家庭医療学])

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8. 楠瀬 賢也

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9. 山田 博胤([徳島大学.大学院医歯薬学研究部.医学域.連携研究部門(医学域).寄附講座系(医学域).地域循環器内科学])

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10. (英) Takeshi Soeki

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11. 若槻 哲三([徳島大学.大学院医歯薬学研究部.医学域.先端医学教育研究プロジェクト]/[徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.循環器内科学]/[徳島大学.病院.診療科.内科.循環器内科])

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12. (英) Imoto Issei

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13. 島袋 充生

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14. 佐田 政隆([徳島大学.大学院医歯薬学研究部.医学域.医科学部門.内科系.循環器内科学])

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(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.

1. (英) Article.ELocationID: CIRCULATIONAHA.118.033544

2. (英) Article.ELocationID: 10.1161/CIRCULATIONAHA.118.033544

3. (英) Article.PublicationTypeList.PublicationType: Journal Article

4. (英) KeywordList.Keyword: atherosclerosis

5. (英) KeywordList.Keyword: inflammation

6. (英) KeywordList.Keyword: macrophage

7. (英) KeywordList.Keyword: protease-activated receptor-2