Absence of p21 Waf1/Cip1/Sdi1 Modulates Macrophage Differentiation and Inflammatory Response and Protects Against Atherosclerosis

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Abstract
Background— The tumor suppressor p53 protects against atherosclerosis progression in several different mouse models. A major target of p53 is p21, the cyclin-dependent kinase inhibitor that regulates entry into the cell cycle of different types of cells, including stem cells. p21 is also involved in the maturation and differentiation of monocytes into macrophages. Methods and Results— We studied the effect of p21 Waf1 inactivation on atherosclerosis development in apolipoprotein E-deficient mice ( apoE − / − ). Contrary to previous data suggesting a protective role for p21, we found that absence of p21, either globally or in bone marrow-derived cells, protects against atherosclerosis. Atherosclerotic lesions of p21 − / − /apoE − / − mice exhibit a more stable phenotype, with increased apoptosis and reduced inflammatory vascular cell adhesion molecule-1 immunostaining but no difference in cellular proliferation compared with lesions of p21 +/+ /apoE − / − mice. Because bone marrow-derived cells mediate many of the effects of p21, we examined the expression profile of 23 genes in macrophages using real-time polymerase chain reaction. Compared with their p21 +/+ counterparts, peritoneal macrophages of p21 − / − mice express lower levels of proinflammatory markers, including macrophage inflammatory proteins 1 and 2 and interleukin-1α, and higher levels of putative protective genes, such as scavenger receptor type B-I and LDL receptor-related protein. Furthermore, we found that, in comparison with p21 +/+ macrophages, p21 − / − macrophages displayed increased phagocytic activity toward fluorescent latex microspheres as well as apoptotic cells, thus uncovering a novel mechanism of the antiinflammatory activity of p21 − / − macrophages. Conclusions— Loss of p21 protects against atherosclerosis in apoE − / − mice. The data underscore the important role of p21 in macrophage function and inflammation and provide insight into the mechanism of the proatherogenic effect of p21.