c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.
c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.
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DOI：
10.1371/journal.pone.0073146
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rodrigues CO
中科院分区：
文献类型：
--
作者：
Florea V;Bhagavatula N;Simovic G;Macedo FY;Fock RA;Rodrigues CO
原癌基因c-Myc对血管发育至关重要，并促进肿瘤血管生成，但其控制血管生长的机制仍不清楚。在目前的工作中，我们研究了c-Myc基因敲低对血管生成所必需的内皮细胞功能的影响，以确定其在血管系统中的作用。我们提供了第一个证据表明，减少c-Myc在内皮细胞中的表达导致促炎衰老表型，特征通常在血管老化和与内皮功能障碍相关的病理过程中观察到。使用表达特异性抗c-Myc shRNA的慢病毒在人脐静脉内皮细胞中敲低c-Myc可减少增殖和管形成。这些功能缺陷与形态学变化、衰老相关β-半乳糖苷酶活性增加、细胞周期抑制剂上调和c-Myc缺陷细胞在G1期的积累相关，表明c-Myc在内皮细胞中的敲低诱导衰老。对c-Myc缺陷型内皮细胞的基因表达分析表明，衰老表型伴随着生长因子、粘附分子、细胞外基质组分和重塑蛋白以及一组促炎介质的显著上调，所述促炎介质包括Angptl 4、Cxcl 12、Mdk、Tgfb 2和Tnfsf 15。在这些细胞因子表达的高峰期，已知参与生长控制的转录因子（E2 f1、Id 1和Myb）下调，而参与炎症反应的转录因子（RelB、Stat 1、Stat 2和Stat 4）上调。我们的研究结果表明c-Myc在预防血管促炎表型中的新作用，支持作为炎症和内皮功能障碍的中央调节器的重要生理功能。
The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb) were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4) were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.
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影响因子：
15.3
作者：
Fang, Lei;Adkins, Becky;Deyev, Vadim;Podack, Eckhard R.
通讯作者：
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影响因子：
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作者：
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DOI：
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影响因子：
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影响因子：
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作者：
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影响因子：
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