Cellular senescence is important in the progression of aging, and targeted elimination of senescent cells has been shown to reverse the course of many age-related conditions in animal studies. Atherosclerosis is the build up of fatty plaques in blood vessels, narrowing and weakening to the point of eventual rupture. This occurs because macrophage cells become dysfunctional and fail in their task of maintaining these tissues. Some macrophages in atherosclerotic plaques are senescent, and these cells, as well as senescent cells in the endothelial and other tissues of blood vessels, produce an inflammatory environment that encourages futher macrophage dysfunction.
Removal of these senescent cells has been shown to slow the progression of atherosclerosis in animal models. Here, researchers investigate one mechanism by which cellular senescence arises in blood vessel endothelial tissues. They show that interfering in this mechanism can reduce the burden of cellular senescence in blood vessel walls, and thus slow the progression of atherosclerosis.
CD9, a tetraspanin membrane protein, is known to regulate cell adhesion and migration, cancer progression and metastasis, immune and allergic responses, and viral infection. CD9 is upregulated in senescent endothelial cells, neointima hyperplasia, and atherosclerotic plaques. However, its role in cellular senescence and atherosclerosis remains undefined.
We investigated the potential mechanism for CD9-mediated cellular senescence and its role in atherosclerotic plaque formation. CD9 knockdown in senescent human umbilical vein endothelial cells significantly rescued senescence phenotypes, while CD9 upregulation in young cells accelerated senescence. CD9 regulated cellular senescence through a phosphatidylinositide 3 kinase-AKT-mTOR-p53 signal pathway. CD9 expression increased in arterial tissues from humans and rats with age, and in atherosclerotic plaques in humans and mice.
Anti-mouse CD9 antibody noticeably prevented the formation of atherosclerotic lesions in ApoE knockout mice and Ldlr knockout mice. Furthermore, CD9 ablation in ApoE knockout mice decreased atherosclerotic lesions in aorta and aortic sinus. These results suggest that CD9 plays critical roles in endothelial cell senescence and consequently the pathogenesis of atherosclerosis, implying that CD9 is a novel target for prevention and treatment of vascular aging and atherosclerosis.