Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis
Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis
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DOI：
10.1172/jci70391
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Leeper, Nicholas J.
中科院分区：
文献类型：
--
作者：
Kojima, Yoko;Downing, Kelly;Leeper, Nicholas J.
染色体9 p21风险位点的遗传变异促进心血管疾病;然而，目前尚不清楚该位点编码的蛋白质如何或哪些有助于疾病。我们以前已经证明，在这个位点的一个候选基因，细胞周期蛋白依赖性ldnase抑制剂2B（Cdkn 2b）的损失，在小鼠中促进血管平滑肌细胞凋亡和动脉瘤的进展。在这里，我们研究了Cdnk 2b在动脉粥样硬化形成中的作用，发现在小鼠动脉粥样硬化模型中，Cdnk 2b的缺失促进了由大的坏死核心组成的动脉粥样硬化斑块的高级发展。此外，9 p21危险等位基因的人类携带者在动脉粥样硬化斑块中CDKN 2B的表达减少，这与钙网蛋白的表达受损有关，钙网蛋白是吞噬细胞上吞噬受体活化所需的配体。作为钙网蛋白减少的结果，CDKN 2B缺陷型凋亡小体对巨噬细胞增多症具有抗性，并且不能被邻近的巨噬细胞有效清除。这些未清除的SMC引起一系列促动脉粥样硬化的阿曲他克林反应，与增加的泡沫细胞形成和炎性细胞因子的制定。外源性钙网蛋白的加入逆转了与Cdkn 2b缺失相关的缺陷，并使Cdkn 2b缺陷细胞的吞噬正常化。总之，这些数据表明，CDKN 2B的丢失通过受损的红细胞增多增加脂质负载的坏死核心的大小和复杂性来促进动脉粥样硬化。
Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent ldnase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2bdeficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis.