PMID- 34422822 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240506 IS - 2296-634X (Print) IS - 2296-634X (Electronic) IS - 2296-634X (Linking) VI - 9 DP - 2021 TI - Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension. PG - 701247 LID - 10.3389/fcell.2021.701247 [doi] LID - 701247 AB - OBJECTIVES: HIF2alpha 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 HIF2alpha 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 HIF2alpha in PAH pathogenesis and the potential to use HIF2alpha-mediated gene sets to differentiate PAH human subjects. METHODS: Using transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2alpha influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2alpha regulatory network in PAH pathogenesis to further determine the identification ability of HIF2alpha-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 HIF2alpha-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2alpha-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments. RESULTS: 19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2alpha-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2alpha-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 and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 (EC-/-) mice compared to WT controls, suggesting opposing effects of HIF2alpha and PHD2 on PAH pathogenesis. CONCLUSION: HIF2alpha-mediated gene sets may be used to differentiate pulmonary arterial hypertension. CI - Copyright (c) 2021 Zhu, Zhao, Hu, Cui, Luo, Bao, Han, Zhou, Lu, Wang, Black and Tang. FAU - Zhu, Jinsheng AU - Zhu J AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Zhao, Li AU - Zhao L AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Hu, Yadan AU - Hu Y AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Cui, Guoqi AU - Cui G AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Luo, Ang AU - Luo A AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Bao, Changlei AU - Bao C AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. FAU - Han, Ying AU - Han Y AD - Department of Physiology, Nanjing Medical University, Nanjing, China. FAU - Zhou, Tong AU - Zhou T AD - Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, United States. FAU - Lu, Wenju AU - Lu W AD - State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. FAU - Wang, Jian AU - Wang J AD - State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. FAU - Black, Stephen M AU - Black SM AD - Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Miami, FL, United States. AD - Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Miami, FL, United States. AD - Center for Translational Science, Florida International University, Port St. Lucie, FL, United States. FAU - Tang, Haiyang AU - Tang H AD - College of Veterinary Medicine, Northwest A&F University, Xianyang, China. AD - State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. LA - eng GR - P01 HL134610/HL/NHLBI NIH HHS/United States GR - P01 HL146369/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20210805 PL - Switzerland TA - Front Cell Dev Biol JT - Frontiers in cell and developmental biology JID - 101630250 PMC - PMC8375387 OTO - NOTNLM OT - HIF2alpha OT - PHD2 OT - hypoxia OT - microarray OT - pulmonary arterial hypertension COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/08/24 06:00 MHDA- 2021/08/24 06:01 PMCR- 2021/01/01 CRDT- 2021/08/23 06:36 PHST- 2021/04/27 00:00 [received] PHST- 2021/07/16 00:00 [accepted] PHST- 2021/08/23 06:36 [entrez] PHST- 2021/08/24 06:00 [pubmed] PHST- 2021/08/24 06:01 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fcell.2021.701247 [doi] PST - epublish SO - Front Cell Dev Biol. 2021 Aug 5;9:701247. doi: 10.3389/fcell.2021.701247. eCollection 2021.