SDPR/Cavin-2 loss inhibits monocyte adhesion to endothelial cells in abdominal aortic aneurysm via suppressing the expression of adhesion molecules. (25th November 2020)

• Record Type: Journal Article
• Authors: Sakamoto, A; Ogata, T; Nakanishi, N; Higuchi, Y; Tsuji, Y; Tomita, S; Matoba, S
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Atherosclerosis, Cerebrovascular Diseases, Aneurysm, Restenosis; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.3794
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Background: Abdominal aortic aneurysm (AAA) is a common and life-threatening vascular disease. The initial phase of AAA progression is vascular inflammation. Inflammation sites present adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1). These molecules play a crucial role in recruiting inflammatory cells to endothelial cells through NF-κB signaling. Endothelial cells express serum deprivation response (SDPR)/Cavin-2 localized in caveolae on the cell membrane. Although Cavin-2 is involved in such as cell proliferation, migration, and signal transduction, the role of Cavin-2 in vascular inflammation in the development of AAA is still unclear. Purpose: To assess the influence of Cavin-2 deficiency in AAA development and clarify the role of Cavin-2 in the regulation of inflammatory cell adhesion in endothelial cells. Methods: CaCl2-induced AAAs were induced by the periaortic application of 0.5 M CaCl2 in male SDPR-knockout (KO) and wild-type (WT) mice at 8–10 weeks of age. Angiotensin II (Ang II)-induced AAAs were created by 4-week-subcutaneous drug infusion in male ApoE-KO and ApoE/Cavin-2-double KO (DKO) mice at 24 weeks of age. Inflammatory response and cell adhesion were evaluated using human aortic endothelial cells (HAECs) and human monocytes (THP-1 cells). Results: Six weeks after CaCl2 treatment, Cavin-2 deficiency significantly attenuated the development of AAAs. Elastin degradation was markedly suppressed and F4/80-positive macrophages infiltration in aortic walls were decreased in Cavin-2-KO mice. Although Ang II infusion for 4 weeks formed AAAs in ApoE KO mice and ApoE/Cavin-2-DKO mice, ApoE/Cavin-2-DKO mice exhibited the suppression of AAA formation independently of blood pressure. Immunohistochemical staining showed VCAM-1 expression on endothelial cells was suppressed in ApoE/Cavin-2-DKO mice. Further, in vitro co-culture experiment, the number of THP-1 cells adhered to TNF-treated SDPR-knockdown HAECs was decreased compared with that to control HAECs. Moreover, mRNA expression of VCAM-1 and ICAM-1 was decreased in TNFα-treated SDPR-knockdown HAECSs. Protein expression of VCAM-1 was also suppressed in TNFα-treated SDPR-knockdown HAECSs. The activity of NF-κB p65, an upstream regulator of VCAM-1 and ICAM-1, tended to be suppressed in TNFα-treated SDPR-knockdown HAECs. Conclusion: In this study, we revealed that SDPR/Cavin-2 loss attenuated AAA development with the suppression of elastin degradation and macrophage infiltration. Our findings suggest that SDPR/Cavin-2 in the endothelial cells regulates the expression of adhesion molecules via NF-κB signaling and promotes the adhesion and infiltration of inflammatory cells to the aortic wall. Funding Acknowledgement: Type of funding source: None