Oligonucleotide microarrays reveal regulated genes related to inward arterial remodeling induced by urokinase plasminogen activator.
Oligonucleotide microarrays reveal regulated genes related to inward arterial remodeling induced by urokinase plasminogen activator.
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寡核苷酸微阵列揭示了与尿激酶纤溶酶原激活剂诱导的内向动脉重塑相关的调节基因。
DOI：
10.1159/000156703
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发表时间：
2009
影响因子：
1.7
通讯作者：
Parfyonova,Yelena
中科院分区：
文献类型：
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作者：
Plekhanova,Olga;Berk,BradfordC;Bashtrykov,Pavel;Brooks,AndrewI;Tkachuk,Vsevolod;Parfyonova,Yelena
越来越多的证据表明，尿激酶型纤溶酶原激活物(UPA)参与了血管成形和支架术后的血管重塑和管腔狭窄。我们以前已经证明，球囊损伤后uPA表达的增加极大地促进了新生内膜的形成和向内的动脉重塑。为了评价炎症在uPA诱导的动脉内向重构的早期机制中的作用，并阐明重构的机制，我们研究了重组uPA治疗后1天和4天大鼠颈动脉损伤后8,799个基因表达谱的变化。我们采用大鼠颈动脉球囊导管损伤的标准模型，然后将uPA溶解于Pluronic凝胶或普通凝胶的外膜外应用于损伤的血管。采用免疫组织化学、形态计量学、微阵列基因表达谱和定量RT-PCR等方法对血管进行分析。在治疗后1天和4天，外周应用uPA显著减少管腔大小和被外弹力板包围的血管面积。UPA治疗后1天和4天，动脉外膜均有炎性细胞聚集。第4天，各动脉层的面积和细胞数均增加。在uPA作用1d后的79个已知差异表达基因中，发现了12个促炎基因，包括肿瘤坏死因子-α和血管紧张素转换酶，以及15个与线粒体代谢和氧化应激调节相关的基因。在uPA处理的动脉损伤后4天，3个致炎基因和2个氧化相关基因有差异表达。我们的结论是，uPA可能通过调节动脉损伤后的氧化应激和炎症而促进动脉内向重塑。
Accumulating evidence suggests that urokinase plasminogen activator (uPA) is involved in vascular remodeling and lumen stenosis after angioplasty and stenting. We have shown previously that increased uPA expression greatly promotes neointima formation and inward arterial remodeling after balloon injury. To evaluate the role of inflammation in early mechanisms responsible for inward arterial remodeling induced by uPA and elucidate the mechanisms of remodeling, we characterized changes in the expression profiles of 8,799 genes in injured rat carotid arteries 1 and 4 days after recombinant uPA treatment compared to vehicle. We used a standard model of the balloon catheter injury of the rat carotid followed by periadventitial application to the injured vessel of either uPA dissolved in Pluronic gel, or plain gel. Vessels were harvested and analyzed by immunohistochemistry, morphometry, microarray gene expression profiling and quantitative RT-PCR. Periadventitial application of uPA significantly reduced lumen size and vessel area encompassed by the external elastic lamina at both 1 and 4 days after treatment. Inflammatory cells accumulated in the arterial adventitia at both 1 and 4 days after uPA treatment. On the 4th day, increases in the areas and arterial cell numbers of all arterial layers were found. Among 79 differentially expressed known genes 1 day after uPA application, 12 proinflammatory genes, including TNF-α and TACE, and 15 genes related to mitochondrial metabolism and oxidative stress regulation were identified. Four days after injury in uPA-treated arteries, 3 proinflammatory and 2 oxidation-related genes were differentially expressed. We conclude that uPA likely promotes inward arterial remodeling by regulating oxidative stress and inflammation after arterial injury.