Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling.
Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling.
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DOI：
10.1093/cvr/cvy206
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发表时间：
2019-01-01
影响因子：
10.8
通讯作者：
Boon RA
中科院分区：
文献类型：
--
作者：
Hofmann P;Sommer J;Theodorou K;Kirchhof L;Fischer A;Li Y;Perisic L;Hedin U;Maegdefessel L;Dimmeler S;Boon RA
长链非编码RNA（lncRNA）已被证明可以调节人类基因组中的许多过程，但这些转录本在血管老化中的功能在很大程度上是未知的。我们的目的是表征lncRNA在内皮老化中的表达，并分析高度保守的lncRNA H19的功能。H19在老龄小鼠内皮细胞中表达下调。在人类中，动脉粥样硬化斑块H19主要由内皮细胞表达，并且与健康颈动脉活检相比，H19显著减少。H19的缺失导致p16和p21的上调，体外增殖减少和衰老增加。幼鼠主动脉环中H19的耗尽抑制发芽能力。我们产生了内皮特异性诱导型H19缺陷小鼠（H19 iEC-KO），与对照同窝出生小鼠（Ctrl）相比，导致收缩压升高。使这些H19 iEC-KO和对照小鼠经受后肢缺血，其显示H19 iEC-KO小鼠中毛细血管密度降低。从机制上讲，外显子阵列分析揭示了H19参与IL-6信号传导。因此，细胞间粘附分子1和血管细胞粘附分子1在H19耗尽后上调。荧光素酶报告基因筛选差异转录因子活性揭示STAT 3被诱导后H19耗尽和抑制后H19过表达。此外，H19的耗竭增加了STAT 3在TYR 705处的磷酸化，并且STAT 3活化的药理学抑制消除了H19沉默对p21和血管细胞粘附分子1表达以及增殖的影响。这些数据揭示了lncRNA H19在控制内皮细胞衰老中的关键作用。
Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
16.6
作者：
Deng Y;Yang Z;Terry T;Pan S;Woodside DG;Wang J;Ruan K;Willerson JT;Dixon RA;Liu Q
通讯作者：
Liu Q
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
64.8
作者：
BARTOLOMEI, MS;ZEMEL, S;TILGHMAN, SM
通讯作者：
TILGHMAN, SM
影响因子：
18.2
作者：
Campisi J
通讯作者：
Campisi J