Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study
Distinct gene expression profiles associated with Notch ligands Delta-like 4 and Jagged1 in plaque material from peripheral artery disease patients: a pilot study
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DOI：
10.1186/s12967-017-1199-3
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发表时间：
2017-05-04
影响因子：
7.4
通讯作者：
Cremonesi, Alberto
中科院分区：
文献类型：
--
作者：
Aquila, Giorgio;Fortini, Cinzia;Cremonesi, Alberto
背景：缺乏早期诊断、进展标志物和有效的药物治疗对外周动脉疾病（PAD）患者的临床结果产生了巨大的不利影响。解决这些问题需要剖析这种疾病背后的分子机制。我们试图表征有症状的PAD患者股骨动脉病变中的Notch信号和动脉粥样硬化相关标志物。方法：采用定向动脉粥样硬化切除术，从20例患者的股总动脉、股浅动脉和腘动脉中取出斑块材料。从20个样本中的9个样本中获得RNA，并通过定量逆转录-聚合酶链反应（qRT-PCR）进行分析。结果：我们检测了Notch配体δ样4 （Dll4）和Jagged1 （Jag1）的表达，Notch靶基因Hes1、Hey1、Hey2、HeyL的表达，以及斑块炎症和稳定性标志物血管细胞粘附分子1 （VCAM1）、平滑肌22 （SM22）、环氧化酶2 （COX2）、Bcl2、CD68和miRNAs 21-5p、125a-5p、126-5p、146-5p、155-5p、424-5p的表达。我们发现了一个“炎症斑块”基因表达谱，其特征是高Dll4与中/高CD68、COX2、VCAM1、Hes1、miR126-5p、miR146a-5p、miR155-5p、miR424-5p相关，低Jag1、SM22、Bcl2、Hey2、HeyL、miR125a相关（2/9例患者），以及高Jag1与中/高Hey2、HeyL、SM22、Bcl2、miR125a相关，低Dll4、CD68、COX2、VCAM1、miR126-5p、miR146a-5p、miR155-5p、miR424-5p相关（3/9例患者）。其余患者（4/9）表现出具有中间特征的斑块特征。结论：本研究揭示了与特定配体激活Notch相关的基因标记的存在，该基因标记可以预测PAD的进展。
Background: The lack of early diagnosis, progression markers and effective pharmacological treatment has dramatic unfavourable effects on clinical outcomes in patients with peripheral artery disease (PAD). Addressing these issues will require dissecting the molecular mechanisms underlying this disease. We sought to characterize the Notch signaling and atherosclerosis relevant markers in lesions from femoral arteries of symptomatic PAD patients.Methods: Plaque material from the common femoral, superficial femoral or popliteal arteries of 20 patients was removed by directional atherectomy. RNA was obtained from 9 out of 20 samples and analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).Results: We detected expression of Notch ligands Delta-like 4 (Dll4) and Jagged1 (Jag1), of Notch target genes Hes1, Hey1, Hey2, HeyL and of markers of plaque inflammation and stability such as vascular cell adhesion molecule 1 (VCAM1), smooth muscle 22 (SM22), cyclooxygenase 2 (COX2), Bcl2, CD68 and miRNAs 21-5p, 125a-5p, 126-5p, 146-5p, 155-5p, 424-5p. We found an "inflamed plaque" gene expression profile characterized by high Dll4 associated to medium/high CD68, COX2, VCAM1, Hes1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p and low Jag1, SM22, Bcl2, Hey2, HeyL, miR125a-5p (2/9 patients) and a "stable plaque" profile characterized by high Jag1 associated to medium/high Hey2, HeyL, SM22, Bcl2, miR125a and low Dll4, CD68, COX2, VCAM1, miR126-5p, miR146a-5p, miR155-5p, miR424-5p (3/9 patients). The remaining patients (4/9) showed a plaque profile with intermediate characteristics.Conclusions: This study reveals the existence of a gene signature associated to Notch activation by specific ligands that could be predictive of PAD progression.