Cyclic AMP response element-binding protein in the vessel wall: good or bad?
Cyclic AMP response element-binding protein in the vessel wall: good or bad?
复制标题
血管壁中的环磷酸腺苷反应元件结合蛋白：好还是坏？
DOI：
10.1161/01.cir.0000084296.45158.50
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Klemm,DwightJ
中科院分区：
文献类型：
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作者：
Reusch,JaneEB;Klemm,DwightJ
通过CREB的显性负性同种型的活性将增加细胞凋亡是预期的结果，与我们实验室（JEB Reusch，MD，and PA沃森，PhD，unpublished data，2003）和许多其它细胞类型和细胞培养系统中进行的研究一致。第二个问题，急性CREB激活血栓形成前基因（凝血酶）和抑制丝裂原刺激的增殖之间的明显差异，可以解释如下。培养物中未受刺激的SMC中CREB功能的丧失不会以稳健的方式影响增殖（两组均观察到）。相比之下，Tokunou等人3在其文章的图5中证明，在用显性阴性CREB处理的血管中，内膜层中BrdU标记适度减少，凋亡细胞死亡显著增加。作者将这种增殖指数的降低解释为显性负性CREB降低SMC增殖的证据。没有明确的组织学证据表明显性阴性CREB感染的细胞是非增殖性的（即双重染色）。内膜增殖减少的另一种解释可能是巨噬细胞和EC的刺激作用丧失。在其他动物模型中，干扰巨噬细胞功能可减少新生内膜损伤的形成。1，2，10，11如果CREB是巨噬细胞终末分化的关键决定因素，那么您可能会看到这些病变中的巨噬细胞积聚较少，因此SMC增殖的有丝分裂原刺激较少。CREB对EC的影响尚不清楚。在球囊损伤模型中，大量病毒被递送到内皮。显性负性CREB可诱导EC凋亡，从而减少EC细胞因子的产生。这将是对所呈现的研究的合理解释，鉴于这种特定的磷酸化缺陷CREB突变体CREBM 1具有正常的DNA结合并且似乎对基础状态下的增殖能力没有影响的事实（图1）。
activity through a dominant negative isoform of CREB would augment apoptosis is an expected result, consistent with studies conducted in our laboratory (JEB Reusch, MD, and PA Watson, PhD, unpublished data, 2003) and in numerous other cell types and cell culture systems. The second issue, the apparent discrepancy between acute CREB activation of prothrombotic genes (thrombin) and restraint of mitogenstimulated proliferation, could be interpreted as follows. Loss of CREB function in unstimulated SMCs in culture does not affect proliferation in a robust way (observed by both groups). In contrast, in Figure 5 of their article, Tokunou et al3 demonstrate a modest decrease in BrdU labeling in the intimal layer and a robust increase in apoptotic cell death in vessels treated with the dominant negative CREB. The authors interpret this decrease in proliferative index as evidence that dominant negative CREB decreases SMC proliferation. There is no clear histological evidence that the cells infected with the dominant negative CREB are nonproliferative (ie, double staining). Another explanation for decreased intimal proliferation could be loss of the stimulatory effects of macrophages and ECs. Interference with macrophage function decreases neointimal lesion formation in other animal models. 1, 2, 10, 11 If CREB is a key determinant of macrophage terminal differentiation, then you might expect to see less macrophage accumulation in these lesions and therefore less mitogen stimulation of SMC proliferation. The impact of CREB on ECs is unknown. In the balloon injury model, a large amount of virus is delivered to the endothelium. Dominant negative CREB could easily induce apoptosis in the ECs and thereby decrease EC cytokine production. This would be a reasonable interpretation of the studies presented, in light of the fact that this particular phosphorylationdeficient CREB mutant, CREBM1, has normal DNA binding and does not appear to have an impact on proliferative capacity in the basal state (Figure 1).