Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension.
Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension.
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缺氧诱导因子 2-α 介导的基因组可区分肺动脉高压
DOI：
10.3389/fcell.2021.701247
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发表时间：
2021
影响因子：
5.5
通讯作者：
Tang H
中科院分区：
文献类型：
--
作者：
Zhu J;Zhao L;Hu Y;Cui G;Luo A;Bao C;Han Y;Zhou T;Lu W;Wang J;Black SM;Tang H
目的HIF 2 α在肺动脉高压时对内皮功能障碍、细胞增殖、迁移和肺血管重构的调节中起重要作用。我们前期的研究表明，条件性和诱导性HIF 2 α基因缺失可显著抑制小鼠肺血管重构和肺动脉高压（PAH）的发生。在这里，我们提供了一个新的转录组的影响，HIF 2 α在PAH发病机制和潜在的使用HIF 2 α介导的基因集区分PAH人类subjects.MethodsUsing转录组数据，我们首先挖掘野生型（WT）和HIF 2a敲低（KD）细胞系之间的基因表达谱的差异的价值。我们认为野生型和HIF 2 α-KD细胞之间的失调基因是HIF 2 α影响的基因。通过检查9名对照和8名PAH患者的肺组织转录组数据集，我们评估了PAH发病机制中的HIF 2 α调控网络，以进一步确定人类PAH受试者中HIF 2 α介导的基因集的识别能力。另一方面，使用PAH患者和健康对照的外周血单核细胞（PBMC）转录组数据，我们进一步验证了HIF 2 α介导的PBMC基因集作为PAH诊断工具的潜力。为验证HIF 2 α介导的基因集对PAH的识别能力，采用内皮细胞特异性Phd 2基因敲除的自发性肺动脉高压小鼠进行反向验证实验。我们进一步评估了这些HIF 2 α介导的基因集在PAH人类受试者中的区分能力。我们发现，肺组织和PBMC中HIF 2 α介导的基因集的表达谱在对照组和PAH患者之间存在差异。此外，缺氧和Phd 2缺陷介导的基因组表达谱之间存在显著正相关。结论HIF 2 α介导的GO基因组与PHD 2基因组在肺动脉高压的发病机制中具有相反的作用，提示HIF 2 α介导的GO基因组与PHD 2基因组在肺动脉高压的发病机制中可能有不同的作用。
ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) andHif2aknockdown (KD) cell lines. We considered the deregulated genes between WT andHif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specificPhd2knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated inHif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia andPhd2deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms inHif2a-KD cells were found to overlap with the up-regulated GO gene sets inPhd2EC–/–mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.
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影响因子：
7
作者：
Guo ML;Kook YH;Shannon CE;Buch S
通讯作者：
Buch S
影响因子：
15.3
作者：
Melillo, Giovanni;Musso, Tiziana;Sica, Antonio;Taylor, Lynn S.;Cox, George W.;Varesio, Luigi
通讯作者：
Varesio, Luigi
影响因子：
20.1
作者：
Kim YM;Barnes EA;Alvira CM;Ying L;Reddy S;Cornfield DN
通讯作者：
Cornfield DN
DOI：
10.1136/amiajnl-2013-002519
发表时间：
2014-11
期刊：
Journal of the American Medical Informatics Association : JAMIA
影响因子：
--
作者：
Gardeux V;Achour I;Li J;Maienschein-Cline M;Li H;Pesce L;Parinandi G;Bahroos N;Winn R;Foster I;Garcia JG;Lussier YA
通讯作者：
Lussier YA
DOI：
10.1096/fj.10-177378
发表时间：
2011-06
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Formenti F;Beer PA;Croft QP;Dorrington KL;Gale DP;Lappin TR;Lucas GS;Maher ER;Maxwell PH;McMullin MF;O'Connor DF;Percy MJ;Pugh CW;Ratcliffe PJ;Smith TG;Talbot NP;Robbins PA
通讯作者：
Robbins PA