ADAM8 Deficiency in Macrophages Alleviates Vascular Calcification in Chronic Kidney Disease.

Abstract

BACKGROUND: Vascular calcification (VC) is an inflammatory disease driven by aberrant cellular processes in which macrophages play an important role. The A disintegrin and metalloproteinase 8 (ADAM8) protein is an important regulatory factor in macrophages and contributes to the development of inflammatory diseases. However, the relationship between ADAM8 and VC remains unknown. Thus, this study aimed to investigate the role of macrophage ADAM8 in VC. METHODS: Plasma ADAM8 levels were compared between patients with and without aortic calcification. Immunofluorescence staining of human aortic tissue samples was performed to assess differences in ADAM8 expression between calcified and non-calcified tissues. Macrophage-specificknockout mice (; KO) and the corresponding control mice (; Flox) were generated using CRISPR/Cas9 technology. Additionally, the adeno-associated virus AAV6-F4/80-was employed to achieve macrophage-specific overexpression. The relationship between macrophage ADAM8 and VC was studied in a VC mouse model of chronic kidney disease (CKD) by comparing VC severity between groups. RESULTS: Plasma ADAM8 levels were elevated in patients with aortic calcification. Immunofluorescence staining of human aortic samples suggested that VC was associated with ADAM8-positive macrophage infiltration and ADAM8 released by macrophages. In mice, macrophage-specificknockout attenuated the development of CKD-associated VC, whereas macrophage-specific ADAM8 overexpression reversed the VC phenotype. CONCLUSION: ADAM8 levels are elevated in patients with aortic calcification and are associated with macrophage infiltration into vascular tissue and ADAM8 release, leading to increased VC. These findings identify ADAM8 as a promising novel therapeutic target for preventing VC.