Polycystin-1 Downregulation Induced Vascular Smooth Muscle Cells Phenotypic Alteration and Extracellular Matrix Remodeling in Thoracic Aortic Dissection.
Polycystin-1 Downregulation Induced Vascular Smooth Muscle Cells Phenotypic Alteration and Extracellular Matrix Remodeling in Thoracic Aortic Dissection.
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胸主动脉夹层中多囊蛋白-1 下调诱导血管平滑肌细胞表型改变和细胞外基质重塑。
DOI：
10.3389/fphys.2020.548055
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发表时间：
2020
影响因子：
4
通讯作者：
Wang LX
中科院分区：
文献类型：
--
作者：
Zhang J;Liu F;He YB;Zhang W;Ma WR;Xing J;Wang LX
多囊蛋白-1 （polycytin -1, PC-1）是由多囊肾病-1 （PKD-1）基因编码的蛋白。本研究旨在探讨PC-1对胸主动脉夹层（TAD）主动脉血管平滑肌细胞（VSMCs）表型和细胞外基质（ECM）功能的调控机制。收集TAD患者和健康对照者的主动脉组织，分离原发性主动脉VSMCs。免疫组织化学、免疫荧光和免疫细胞化学用于观察目标蛋白。采用Western blot和RT-qPCR检测mRNA和蛋白的表达。慢病毒感染可下调或过表达PC-1。与对照组相比，TAD组VSMCs的PC-1和收缩表型标志物的表达降低，而VSMCs合成标志物、基质金属蛋白酶(MMP)-2、I型胶原和III型胶原的表达升高。TAD组mTOR、S6K和S6的磷酸化水平也升高。与对照组相比，PC-1下调主动脉VSMCs抑制了收缩标志物的表达，但提高了合成标志物、MMP-2、I型胶原和III型胶原的表达。在pkd -1敲低的VSMCs中，mTOR、S6K和S6的磷酸化也增加。PC-1的上调逆转了主动脉VSMCs中所有这些表达特征。此外，雷帕霉素对pkd -1敲低的VSMCs的处理抑制了PC-1下调引起的影响。我们的研究发现，PC-1下调通过激活mTOR/S6K/S6信号通路诱导主动脉VSMCs表型改变和ECM重塑。PC-1的下调可能是TAD发生发展的潜在机制。雷帕霉素可能是一种潜在的抑制TAD发生和发展的抑制剂。
Polycystin-1 (PC-1) is a protein encoded by the gene of polycystic kidney disease-1 (PKD-1). This study was designed to investigate the regulatory mechanisms of PC-1 on phenotypes of aortic vascular smooth muscle cells (VSMCs) and functions of extracellular matrix (ECM) in thoracic aortic dissection (TAD). Aortic tissues from patients with TAD and healthy controls were collected, primary aortic VSMCs were also isolated. Immunohistochemistry, immunofluorescence, and immunocytochemistry was used to visualize the target proteins. Western blot and RT-qPCR were used to examine the expression of mRNA and proteins. Lentivirus infection was used to downregulate or overexpress PC-1. Compared with the control group, expression of PC-1 and the contractile phenotypic markers of VSMCs were decreased in TAD group, whereas expression of the synthetic markers of VSMCs, matrix metalloproteinase (MMP)-2, collagen I and collagen III were increased. The phosphorylation of mTOR, S6K and S6 were also elevated in TAD group. PC-1 downregulation of aortic VSMCs inhibited the expression of the contractile markers, but elevated the expression of the synthetic markers, MMP-2, collagen I and collagen III compared with the control group. The phosphorylation of mTOR, S6K and S6 were also increased in PKD-1-knockdown VSMCs. PC-1 upregulation reversed all these expression characteristics in aortic VSMCs. Furthermore, rapamycin treatment to PKD-1-knockdown VSMCs inhibited the effects caused by PC-1 downregulation. Our study revealed PC-1 downregulation induces aortic VSMCs phenotypic alteration and ECM remodeling via activation of mTOR/S6K/S6 signaling pathway. Downregulation of PC-1 might be a potential mechanism for the development and progression of TAD. Rapamycin might be a potential inhibitor to attenuate the development and progression of TAD.
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影响因子：
3.3
作者：
Borges, Luciano F.;Touat, Ziad;Michel, Jean-Baptiste
通讯作者：
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影响因子：
5.3
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Papavassiliou, Kostas A.;Zoi, Ilianna;Koutsilieris, Michael
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Koutsilieris, Michael
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3.3
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影响因子：
81.5
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通讯作者：
Pepper, John
影响因子：
20.1
作者：
Pankratz, Franziska;Hohnloser, Catherine;Grundmann, Sebastian
通讯作者：
Grundmann, Sebastian