Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation.
Loss of CDKN2B promotes p53-dependent smooth muscle cell apoptosis and aneurysm formation.
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DOI：
10.1161/atvbaha.112.300399
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发表时间：
2013-01
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影响因子：
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通讯作者：
Quertermous T
中科院分区：
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作者：
Leeper NJ;Raiesdana A;Kojima Y;Kundu RK;Cheng H;Maegdefessel L;Toh R;Ahn GO;Ali ZA;Anderson DR;Miller CL;Roberts SC;Spin JM;de Almeida PE;Wu JC;Xu B;Cheng K;Quertermous M;Kundu S;Kortekaas KE;Berzin E;Downing KP;Dalman RL;Tsao PS;Schadt EE;Owens GK;Quertermous T
全基因组关联研究表明，9p21.3的等位基因变异与多种形式的血管疾病有关，包括动脉粥样硬化性冠心病和腹主动脉瘤。至于9p21.3的其他基因，人类eQTL研究已经发现肿瘤抑制基因CDKN2B的表达与风险单倍型有关，但其在血管病理生物学中的潜在作用尚不清楚。在这里，我们采用了血管损伤模型，发现CDKN2B基因敲除小鼠在损伤后表现出预期的增殖增加，但出现了较少的新生内膜病变和更大的主动脉瘤。原位和体外研究表明，这些作用是由于增加了平滑肌细胞的凋亡。过继的骨髓移植研究证实，CDKN2B的观察到的作用是通过内在血管细胞介导的，并不依赖于骨髓来源的炎症细胞。机制研究表明，观察到的细胞凋亡增加是由于MDM2的减少和p53信号的增加，可能部分是由于9p21.3基因的其他基因的补偿。CDKN2B和P53的双重抑制导致了每个模型中血管表型的逆转。这些结果提示CDKN2B表达降低和SMC凋亡增加可能是9p21.3与动脉瘤疾病相关的机制之一。
Genome wide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As for other genes at 9p21.3, human eQTL studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear. Here we employed vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were due to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was due to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model. These results suggest that reduced CDKN2B expression and increased SMC apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.