Abstract 1149: Angiotensin II-Induced Vascular Cell Senescence Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway
Vascular cells have a finite lifespan and eventually enter cell growth arrest, cellular senescence. We demonstrated that vascular cell senescence in vivo contributes to age-related vascular disorders. Recently we have reported that constitutive activation of Ras causes vascular cell senescence and vascular inflammation in human atherosclerosis. In this study, we examined whether angiotensin II (AII), a potent activator of Ras, induces vascular cell senescence, thereby contributing to atherogenesis. AII increased transcriptional activity of p53 and thus upregulated expression of p21 in human vascular smooth muscle cells (HSMC). Senescence-associated b-galactosidase activity, a marker for cellular senescence, was significantly increased by AII. Activation of the p53/p21 pathway mediates expression of the cytokines, as well as cellular senescence induced by AII. Forced expression of p21 increased activity of nuclear factor kB, an important transactivator of inflammatory cytokines, by inducing the production of reactive oxygen species. Treatment of apolipoprotein E (apoE) knockout (KO) mice with AII induced expression of p21 and accelerated not only vascular cell senescence but also severe aneurysmal formation in the aorta. To determine whether AII-induced vascular cell senescence contributes to the progression of atherosclerosis, we generated apoE/p21 double KO mice and examined the effects of AII. Senescent vascular cells were significantly decreased in the aortas of double KO mice compared with those of apoE KO mice. Ablation of p21 effectively reduced the development of aneurysmal formation and the incidence of rupture induced by AII treatment. Pro-inflammatory molecules such as cytokines and metalloproteinases were markedly elevated in the aortas of apoE KO after AII treatment, which was significantly reduced by p21-deficiency. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by AII. These data suggest that AII induces vascular cell senescence and thus contributes to the development of atherosclerosis through the p53/p21 pathway.