Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE*3-Leiden transgenic mice

Cell proliferation and cell death (either necrosis or apoptosis) are key pr ocesses in the progression of atherosclerosis. The tumor suppressor gene p5 3 is an essential gene in cell proliferation and cell death and is upregula ted in human atherosclerotic plaques, both in smooth muscle cells and in ma crophages. In the present study, we investigated the importance of macropha ge p53 in the progression of atherosclerosis using bone marrow transplantat ion in APOE*3-Leiden transgenic mice, an animal model for human-like athero sclerosis, APOE*3-Leiden mice were lethally irradiated and reconstituted wi th bone marrow derived from either p53-deficient (p53(-/-)) or control (p53 (+/+)) donor mice. Reconstitution of mice with p53(-/-) bone marrow did not result in any hemopoietic abnormalities as compared with p53(+/+) transpla nted mice. After 12 weeks on an atherogenic diet, APOE*3-Leiden mice recons tituted with p53(-/-) bone marrow showed a significant (P=0.006) 2.3-fold i ncrease in total atherosclerotic lesion area as compared with mice reconsti tuted with p53(+/+) bone marrow. Although likely a secondary effect of the increased lesion area, p53(-/-) transplanted mice also showed significantly more lesion necrosis (necrotic index, 1.1+/-1.3 versus 0.2+/-0.7; P=0.04) and lesion macrophages (macrophage area, 79.9+/-40.0 versus 39.7+/-27.3x10( 3) mum(2) per section; P=0.02), These observations coincided with a tendenc y toward decreased apoptosis (terminal deoxynucleotidyl transferase end-lab eling [TUNEL]-positive nuclei going from 0.42 +/- 0.39 to 0.14+/-0.15%, P=0 .071), whereas the number of proliferating cells (5'-bromo-2'-deoxyuridine- positive nuclei) was not affected (3.75 +/- 0.98 versus 4.77 +/- 2.30%; P = 0.59). These studies indicate that macrophage p53 is important in suppress ing the progression of atherosclerosis and identify a novel therapeutic tar get for regulating plaque stability.