ADAMDEC-1 promotes atherosclerosis progression by interacting with ACTN4 and modulating the PTEN-PI3K/AKT signaling...

Atherosclerosis (AS) is a chronic vascular disease process that accounts for a large share of cardiovascular morbidity, and substantial risk remains even when currently available therapies are used. ADAMDEC-1, also referred to as ADAM-like decysin-1, has mainly been discussed in mucosal and intestinal immune regulation. Its involvement in vascular injury has not been adequately defined. This study was designed to determine whether ADAMDEC-1 contributes to AS and to map the signaling mechanism responsible for this effect. ADAMDEC-1 was suppressed in an experimental AS mouse model by AAV-mediated shRNA delivery. In parallel, cultured human vascular smooth muscle cells (HVSMCs) were stimulated with oxidized low-density lipoprotein (ox-LDL) to reproduce pro-atherosclerotic cellular stress. Protein expression, protein interaction, subcellular localization, cell proliferative capacity, migration, and cell-cycle changes were assessed using Western blotting, IP-MS, Co-IP, immunofluorescence, CCK-8, Transwell, scratch wound-healing, and flow-cytometry assays. ADAMDEC-1 knockdown reduced aortic lesion burden and was accompanied by increased HDL and decreased LDL and triglyceride levels in AS mice. Qualitative IP-MS screening identified ACTN4 as a candidate ADAMDEC-1-interacting protein, and their association was supported by Co-IP. Ox-LDL treatment also increased the cellular colocalization of ADAMDEC-1 and ACTN4. In aortic tissues, ADAMDEC-1 knockdown was accompanied by reduced ACTN4 abundance, restored PTEN expression, and attenuated PI3K/AKT phosphorylation. In HVSMCs, ACTN4 knockdown reduced ox-LDL-induced cell proliferative capacity, migration, cell-cycle redistribution, and expression of PCNA, MMP2, and MMP9. These findings indicate that ADAMDEC-1 contributes to experimental AS and is associated with ACTN4 and PTEN/PI3K/AKT signaling. ACTN4 is required for the full ox-LDL-induced phenotype in HVSMCs.