Macrophage-Specific p53 Expression Plays a Crucial Role in Atherosclerosis Development and Plaque Remodeling

Abstract

Objective-We first showed that absence of p53 accelerates atherosclerosis development in apoE-deficient mice. In this study, we investigated how macrophage-specific loss of p53 function might modulate atherosclerosis development in LDL receptor-deficient mice, a model for familial hypercholesterolemia. Methods and Results-We transferred bone marrow cells isolated from p53ϩ/ϩ and p53 Ϫ/Ϫ mice to lethally irradiated LDL receptor Ϫ/Ϫ mice and evaluated the aortic atherosclerotic lesion areas in the recipients at different times afterward. At 15 weeks and again at 20 weeks, we found larger aortic lesion size in mice receiving p53Ϫ/Ϫ cells compared with those that received p53 ϩ/ϩ cells. By measuring the rate of bromodeoxyuridine incorporation, we found that the absence of p53 in macrophages stimulates cellular proliferation. In contrast, the rate of apoptosis in the atheromatous lesion was similar in the two groups of mice. Furthermore, we found that the absence of macrophage-specific p53 expression was associated with vulnerable-appearing lesions marked by increased tissue necrosis and reduced collagen deposition. Conclusions-p53 plays a crucial role in atherosclerosis lesion development and remodeling, and macrophage-specific p53 deficiency stimulates cellular proliferation leading to a

Unexpected Proatherogenic Properties of p21

“…p53 Ϫ/Ϫ apoE Ϫ/Ϫ mice disclosed a significant increase in arterial cell proliferation with no significant changes in apoptosis. The main findings of this study have been extended by the demonstration that reconstitution of irradiated LDL receptor-null mice 8 or apoE*3-Leiden transgenic mice 9 with p53-null bone marrowderived cells also accelerates atherosclerosis. Likewise, p27 inactivation, either globally 10 or in bone marrow-derived cells, 11 increases arterial cell proliferation and accelerates arteriosclerosis in fat-fed apoE-null mice.…”

“…Thus, in contrast to the reported intensification of atherosclerosis achieved on p27 or p53 inactivation in different induced murine models, [7][8][9][10][11] Merched and Chan 12 convincingly establish that p21 ablation, either globally or selectively in hematopoietic precursors, reduces both spontaneous and diet-induced atherosclerosis in apoE-null mice examined at different ages and under different nutritional regimens. Because transplantation of p21-null bone marrow cells into irradiated apoE-null mice reproduced most of the protective effect of whole-body p21 inactivation, including a thicker and better-formed fibrous cap, it was concluded that the absence of p21 expression in the neointimal macrophages is important to the beneficial effect against atherosclerosis.…”

Long Noncoding RNAs in Atherosclerosis

“…As an essential and most important molecule in cell cycle and apoptosis control, p53 also plays a critical role in atherosclerosis [53][54][55] . Several studies demonstrated that the development of atherosclerosis was accompanied with the inactivation of p53 [56][57][58] .…”

p53 and disease: when the guardian angel fails

“…73 In this mouse model for familial hypercholesterolemia, loss of p53 stimulated proliferation in macrophages and was associated with unstable lesions, increased necrosis and with reduced collagen deposition, all bad prognostic features. 74 Macrophage migration into the fatty core of the plaque plays an important role in the genesis of dangerous lesions.…”