An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway

Cyanotic congenital heart disease (CCHD), a term describing the most severe congenital heart diseases are characterized by the anatomic malformation of a right to left shunt. Although the incidence of CCHD are far less than the that of congenital heart diseases (CHD), patients with CCHD always prese...

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Main Authors: Yuanlin Zhou, Na Ouyang, Lingjuan Liu, Jie Tian, Xupei Huang, Tiewei Lu
Format: Article
Language:English
Published: KeAi Communications Co., Ltd. 2019-03-01
Series:Genes and Diseases
Online Access:http://www.sciencedirect.com/science/article/pii/S2352304218300412
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author Yuanlin Zhou
Na Ouyang
Lingjuan Liu
Jie Tian
Xupei Huang
Tiewei Lu
author_facet Yuanlin Zhou
Na Ouyang
Lingjuan Liu
Jie Tian
Xupei Huang
Tiewei Lu
author_sort Yuanlin Zhou
collection DOAJ
description Cyanotic congenital heart disease (CCHD), a term describing the most severe congenital heart diseases are characterized by the anatomic malformation of a right to left shunt. Although the incidence of CCHD are far less than the that of congenital heart diseases (CHD), patients with CCHD always present severe clinical features such as hypoxia, dyspnea, and heart failure. Chronic hypoxia induces hypoxemia that significantly contributes to poor prognosis in CCHD. Current studies have demonstrated that the prolyl-4-hydroxylase2 (PHD2, encoded by EGLN1)/hypoxia-inducible factor-1A (HIF-1A) pathway is a key regulator of hypoxic response. Thus, we aim to assess the associations of single polymorphisms (SNPs) of the EGLN1 gene and hypoxic response in CCHD. A missense variant of EGLN1 c.380G>C (rs1209790) was found in 46 patients (46/126), with lower hypoxia incidence and higher rate of collateral vessel formation, compared with the wild type (P < 0.05). In vitro experiments, during hypoxia, EGLN1 mutation reduced EGLN1 expression compared with the wild type, with higher HIF-1A, VEGF and EPO expression levels in the mutant. No difference in HK1 expression was observed between the mutant and wild type. CCHD patients with c.380G>C showed improved response to hypoxia compared with the wild-type counterparts. The EGLN1 c.380G>C mutation improves hypoxic response through the PHD2/HIF-1A pathway, which may provide a molecular mechanism for hypoxic response in CCHD. The effects of the EGLN1 c.380G>C mutation on CCHD prognosis deserve further investigation. Keywords: Cyanotic congenital heart disease, EGLN1, Hypoxic response, Mutation, Polymorphism
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spelling doaj.art-8677f0cb421f4a2892f116927d5784f52023-09-02T12:08:29ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422019-03-01613542An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathwayYuanlin Zhou0Na Ouyang1Lingjuan Liu2Jie Tian3Xupei Huang4Tiewei Lu5Department of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR ChinaDepartment of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR ChinaDepartment of Biomedical Science, Charlie E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USADepartment of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China; Key Laboratory of Developmental Disease in Childhood (Chongqing Medical University), Ministry of Education, Chongqing, PR China; Key Laboratory of Pediatrics in Chongqing, Chongqing, PR China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, PR China; Corresponding author. Department of Cardiology, Children's Hospital of Chongqing Medical University, Chongqing, PR China.Cyanotic congenital heart disease (CCHD), a term describing the most severe congenital heart diseases are characterized by the anatomic malformation of a right to left shunt. Although the incidence of CCHD are far less than the that of congenital heart diseases (CHD), patients with CCHD always present severe clinical features such as hypoxia, dyspnea, and heart failure. Chronic hypoxia induces hypoxemia that significantly contributes to poor prognosis in CCHD. Current studies have demonstrated that the prolyl-4-hydroxylase2 (PHD2, encoded by EGLN1)/hypoxia-inducible factor-1A (HIF-1A) pathway is a key regulator of hypoxic response. Thus, we aim to assess the associations of single polymorphisms (SNPs) of the EGLN1 gene and hypoxic response in CCHD. A missense variant of EGLN1 c.380G>C (rs1209790) was found in 46 patients (46/126), with lower hypoxia incidence and higher rate of collateral vessel formation, compared with the wild type (P < 0.05). In vitro experiments, during hypoxia, EGLN1 mutation reduced EGLN1 expression compared with the wild type, with higher HIF-1A, VEGF and EPO expression levels in the mutant. No difference in HK1 expression was observed between the mutant and wild type. CCHD patients with c.380G>C showed improved response to hypoxia compared with the wild-type counterparts. The EGLN1 c.380G>C mutation improves hypoxic response through the PHD2/HIF-1A pathway, which may provide a molecular mechanism for hypoxic response in CCHD. The effects of the EGLN1 c.380G>C mutation on CCHD prognosis deserve further investigation. Keywords: Cyanotic congenital heart disease, EGLN1, Hypoxic response, Mutation, Polymorphismhttp://www.sciencedirect.com/science/article/pii/S2352304218300412
spellingShingle Yuanlin Zhou
Na Ouyang
Lingjuan Liu
Jie Tian
Xupei Huang
Tiewei Lu
An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
Genes and Diseases
title An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
title_full An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
title_fullStr An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
title_full_unstemmed An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
title_short An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway
title_sort egln1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the phd2 hif 1a pathway
url http://www.sciencedirect.com/science/article/pii/S2352304218300412
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