Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by the CCL3–CCR5 axis

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03957
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Ishida Yuko 和歌山県立医科大学, 医学部, 准教授 (10364077)
• Co-Investigator(Kenkyū-buntansha): 野坂 みずほ 和歌山県立医科大学, 医学部, 講師 (00244731)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 大動脈瘤 / 突然死

Outline of Final Research Achievements

We report that CaCl2 application into abdominal aorta induces abdominal aortic aneurysm (AAA) with intra-aortic infiltration of macrophages as well as enhanced expression of CCL3 and MMP-9. Moreover, infiltrating macrophages express CCR5 and MMP-9. Both Ccl3-/- mice and Ccr5-/- but not Ccr1-/- mice exhibit exaggerated CaCl2-inducced AAA with augmented macrophage infiltration and MMP-9 expression. Immunoneutralization of CCL3 mimics the phenotypes observed in CaCl2-treated Ccl3-/- mice. On the contrary, CCL3 treatment attenuates CaCl2-induced AAA in both wild-type and Ccl3-/- mice. Consistently, we find that the CCL3-CCR5 axis suppresses PMA-induced enhancement of MMP-9 expression in macrophages. Thus, CCL3 can be effective to prevent the development of CaCl2-induced AAA by suppressing MMP-9 expression.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

我々の実験的研究は、CCL3-CCR5経路がAAA形成において保護的な役割を果たしていることを示している。白人のかなりの割合がヒトCCR5遺伝子にΔ32と呼ばれる32塩基対の欠失対立遺伝子を有しており、CCR5 Δ32変異を持つホモ接合体は、Ccr5-/-マウスと同様に機能的なCCR5タンパク質を発現しない。CCR5 Δ32変異はAAAの発症率を増加させたが、これはCaCl2-あるいはAngiotensin IIで処理したCcr5-/-マウスにおける我々の観察と一致していた。したがって、動脈瘤に対するCCL3の治療活性を検討することは妥当である。