Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice.
Recent studies have indicated that the tumor suppressor gene p53 limits atherosclerosis in animal models; p53 expression is also increased in advanced human plaques compared with normal vessels, where it may induce growth arrest and apoptosis. However, controversy exists as to the role of endogenous levels of p53 in different cell types that comprise plaques. We examined atherosclerotic plaque development and composition in brachiocephalic arteries and aortas of p53-/-/ApoE-/- mice versus wild type p53 controls. p53-/- mice demonstrated increased aortic plaque formation, with increased rates of cell proliferation and reduced rates of apoptosis in brachiocephalic arteries. Although most proliferating cells were monocyte/macrophages, apoptotic cells were both vascular smooth muscle cells (VSMCs) and macrophages. Transplant of p53 bone marrow to p53-/-/ApoE-/- mice reduced aortic plaque formation and cell proliferation in brachiocephalic plaques, but also markedly reduced apoptosis. To examine p53 regulation of these processes, we studied proliferation and apoptosis in macrophages, bone marrow stromal cells and VSMCs cultured from these mice. Although endogenous p53 promoted apoptosis in macrophages, it protected VSMCs and stromal cells from death, a hitherto unknown function in these cells, in part by inhibiting DNA damage response enzymes. p53 also inhibited stromal cell expression of VSMC markers. We conclude that endogenous levels of p53 protect VSMCs and stromal cells against apoptosis, while promoting apoptosis in macrophages, and protect against atherosclerosis development.
Mercer
John
J
Division of Cardiovascular Medicine, University of Cambridge, PO Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Figg
Nichola
N
Stoneman
Victoria
V
Braganza
Denise
D
Bennett
Martin R
MR
D000818:Animals; D001011:Aorta / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D016122:Brachiocephalic Trunk / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D004036:Diet, Atherogenic; D005260:Female; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D011828:Radiation Chimera; D017154:Stromal Cells / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D001057:Apolipoproteins E; D015415:Biomarkers; D016159:Tumor Suppressor Protein p53