Nuclear factor of activated T cells 5 regulates vascular smooth muscle cell phenotypic modulation.
Nuclear factor of activated T cells 5 regulates vascular smooth muscle cell phenotypic modulation.
复制标题
DOI：
10.1161/atvbaha.111.232165
复制
发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Wamhoff BR
中科院分区：
文献类型：
--
作者：
Halterman JA;Kwon HM;Zargham R;Bortz PD;Wamhoff BR
张力响应转录因子，活化t细胞核因子5 (NFAT5/TonEBP)，已经在许多细胞类型中得到了很好的表征；然而，NFAT5在血管平滑肌细胞（SMCs）中的功能尚不清楚。我们的主要目的是确定NFAT5调控在SMCs中的作用。我们发现，在SMCs中，NFAT5受高渗性调节，在动脉粥样硬化和新生内膜增生中上调。RNAi敲低NFAT5可抑制几种SMC分化标记基因的基础表达，包括平滑肌α -肌动蛋白（SMαA）。生物信息学分析显示SMαA在第一个内含子上有7个推测的NFAT5结合位点，ChIP分析显示内含子DNA中有NFAT5富集。过表达NFAT5增加了SMαA启动子内含子活性，这需要一个+1012的NFAT5顺式元件，而显性负表达NFAT5则降低了SMαA启动子内含子活性。由于SMCs不太可能经历张力的极端变化，我们研究了其他刺激并发现了两种新的nfat5诱导因子：血管紧张素II（一种收缩激动剂）和血小板衍生生长因子- bb (PDGF-BB)，一种血管损伤中的有效丝裂原。血管紧张素II刺激NFAT5易位和活性，NFAT5敲低抑制血管紧张素II介导的SMαA mRNA上调。PDGF-BB增加NFAT5蛋白，NFAT5的缺失抑制PDGF-BB诱导的SMC迁移。我们已经确定NFAT5是SMC表型调节的新调节剂，并揭示了NFAT5在血管紧张素ii诱导的SMαA表达和pdgf - bb刺激的SMC迁移中的作用。
The tonicity-responsive transcription factor, nuclear factor of activated T-cells 5 (NFAT5/TonEBP), has been well characterized in numerous cell types; however, NFAT5 function in vascular smooth muscle cells (SMCs) is unknown. Our main objective was to determine the role of NFAT5 regulation in SMCs. We show that NFAT5 is regulated by hypertonicity in SMCs and is upregulated in atherosclerosis and neointimal hyperplasia. RNAi knockdown of NFAT5 inhibits basal expression of several SMC differentiation marker genes, including smooth muscle alpha actin (SMαA). Bioinformatic analysis of SMαA reveals seven putative NFAT5 binding sites in the first intron, and ChIP analysis shows NFAT5 enrichment of intronic DNA. Overexpression of NFAT5 increases SMαA promoter-intron activity, which requires an NFAT5 cis element at +1012, while dominant-negative NFAT5 decreases SMαA promoter-intron activity. Since it is unlikely that SMCs experience extreme changes in tonicity, we investigated other stimuli and uncovered two novel NFAT5-inducing factors: angiotensin II, a contractile agonist, and platelet-derived growth factor-BB (PDGF-BB), a potent mitogen in vascular injury. Angiotensin II stimulates NFAT5 translocation and activity, and NFAT5 knockdown inhibits an angiotensin II-mediated upregulation of SMαA mRNA. PDGF-BB increases NFAT5 protein and loss of NFAT5 inhibits PDGF-BB-induced SMC migration. We have identified NFAT5 as a novel regulator of SMC phenotypic modulation and have uncovered the role of NFAT5 in angiotensin II-induced SMαA expression and PDGF-BB-stimulated SMC migration.