Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions

被引：2

作者：

Koga, Jun-ichiro ^{[1
,2
]}

Umezu, Ryuta ^{[2
]}

Kondo, Yuki ^{[1
,3
]}

Shirouzu, Tomohiro ^{[1
]}

Orkhonselenge, Nasanbadrakh ^{[1
]}

Ueno, Hiromichi ^{[1
]}

Katsuki, Shunsuke ^{[2
]}

Matoba, Tetsuya ^{[2
]}

Nishimura, Yosuke ^{[3
]}

Kataoka, Masaharu ^{[1
]}

机构：

[1] Univ Occupat & Environm Hlth, Dept Internal Med 2, 1-1 Iseigaoka,Yahatanishi Ku, Kitakyushu 8078555, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka, Japan

[3] Univ Occupat & Environm Hlth, Dept Cardiovasc Surg, Kitakyushu, Japan

来源：

ATHEROSCLEROSIS | 2024年 / 396卷

关键词：

Atherosclerosis; Macrophages; Apoptosis; Necrotic core; Cyclophilin D; RISK-ASSESSMENT STRATEGIES; PERMEABILITY TRANSITION; VULNERABLE PATIENT; PLAQUE NECROSIS; CORONARY; INFLAMMATION; CYCLOSPORINE; DEFINITIONS; PROGRESSION; APOPTOSIS;

D O I：

10.1016/j.atherosclerosis.2024.118524

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background and aims: In advanced atherosclerotic lesions, macrophage deaths result in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. Therefore, this experiment aims to clarify the role of CypD in necrotic core formation. Methods: To clarify the specific role of CypD, encoded by Ppif in mice, apolipoprotein-E/CypD-double knockout (Apoe- /-Ppif- /- ) mice were generated. These mice were fed a high-fat diet containing 0.15 % cholesterol for 24 weeks to accelerate atherosclerotic lesion development. Results: Deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control Apoe- /- mice. In RAW264.7 cells, siRNA-mediated knockdown of CypD attenuated the release of cytochrome c from the mitochondria to the cytosol induced by endoplasmic reticulum stress inducer thapsigargin. In addition, necroptosis, induced by TNF-alpha and caspase inhibitor, was attenuated by knockdown of CypD. Ly-6Chigh inflammatory monocytes in peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-gamma, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. Conclusions: These results indicate that CypD induces macrophage death and mediates necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

引用

页数：9