Mercer John, Figg Nichola, Stoneman Victoria, Braganza Denise, Bennett Martin R
Division of Cardiovascular Medicine, University of Cambridge, PO Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK.
Circ Res. 2005 Apr 1;96(6):667-74. doi: 10.1161/01.RES.0000161069.15577.ca. Epub 2005 Mar 3.
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.
近期研究表明，肿瘤抑制基因p53在动物模型中可限制动脉粥样硬化；与正常血管相比，p53在人类晚期斑块中的表达也会增加，在正常血管中它可能诱导生长停滞和细胞凋亡。然而，关于内源性p53水平在构成斑块的不同细胞类型中的作用仍存在争议。我们研究了p53基因敲除/ApoE基因敲除小鼠与野生型p53对照小鼠的头臂动脉和主动脉中动脉粥样硬化斑块的发展及组成。p53基因敲除小鼠的主动脉斑块形成增加，头臂动脉中的细胞增殖速率增加而细胞凋亡速率降低。虽然大多数增殖细胞是单核细胞/巨噬细胞，但凋亡细胞包括血管平滑肌细胞（VSMC）和巨噬细胞。将p53骨髓移植到p53基因敲除/ApoE基因敲除小鼠可减少主动脉斑块形成以及头臂斑块中的细胞增殖，但也显著降低了细胞凋亡。为了研究p53对这些过程的调控，我们研究了从这些小鼠培养的巨噬细胞、骨髓基质细胞和VSMC中的增殖和凋亡。虽然内源性p53促进巨噬细胞凋亡，但它保护VSMC和基质细胞免于死亡，这在这些细胞中是一种迄今未知的功能，部分是通过抑制DNA损伤反应酶来实现的。p53还抑制基质细胞中VSMC标志物的表达。我们得出结论，内源性p53水平可保护VSMC和基质细胞免于凋亡，同时促进巨噬细胞凋亡，并预防动脉粥样硬化的发展。
