Endothelial JAML inhibits inflammation and atherosclerosis through TRIM25-mediated STAT1 ubiquitination

Atherosclerosis is a chronic inflammatory disease initiated by endothelial dysfunction. Junctional adhesion molecule-like protein (JAML) is known to regulate inflammatory responses; however, its function in vascular endothelial cells and atherosclerosis remains unclear. This study aimed to investigate the function of endothelial JAML in atherosclerosis and to uncover the molecular mechanisms involved.

We generated mice with specific deletion of JAML in endothelial cells and fed them a high-fat diet to induce atherosclerosis, then assessed plaque formation in the aortic root and entire aorta. In parallel, endothelial cells were treated with tumor necrosis factor alpha, and the effects of increasing or silencing JAML on adhesion molecule expression were evaluated, with protein interactions analyzed by co-immunoprecipitation and immunoblotting.

JAML exhibited downregulation in endothelial cells within both atherosclerotic lesions and cultured cells subjected to inflammatory stimuli. In mice, the loss of JAML resulted in exacerbated atherosclerotic progression, characterized by larger plaque formation, increased vascular inflammation, and increased macrophage infiltration. Conversely, overexpression of JAML attenuated the expression of adhesion molecules. Mechanistically, JAML was found to promote the degradation of signal transducer and activator of transcription 1 (STAT1) by facilitating its interaction with the E3 ubiquitin ligase tripartite motif-containing 25. This interaction led to ubiquitin-mediated proteolysis of STAT1, independent of alterations in its gene expression levels.

These findings suggest that endothelial JAML holds significant promise as a novel therapeutic target for the prevention and intervention of atherosclerosis.