Cell Signal. 2026 Feb 12:112412. doi: 10.1016/j.cellsig.2026.112412. Online ahead of print.
ABSTRACT
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE-/- mouse model of carotid atherosclerosis via high-fat diet feeding combined with surgical intervention, with thickened fibrous caps, reduced lipid deposition and decreased immune cell infiltration. These protective effects were abolished upon co-administration of SB431542. Immunofluorescence and western blot analyses of clinical samples corroborated that AMIGO1 enhances carotid plaque stability by upregulating TGFRII level. Our collective data indicated that AMIGO1 regulated stability of plaque by promoting endothelial cell adhesion and downregulating inflammatory cytokines production through activating TGFβ/SMAD pathway via interacting with TGFRII. This study provides a critical theoretical foundation for developing clinical therapies and novel targets for CAS.
PMID:41690437 | DOI:10.1016/j.cellsig.2026.112412