Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism

Wu, Tao; Zhang, Biqi; Raelson, John; Yao, Yumei; Wu, Huandong; Xu, Zhifei; Marois-Blanchet, François-Christophe; Tahir, Ramzan; Wang, Yujia; Bradley, Wayne E.; Luo, Hongyu; Wu, Jiangping; Sheng, Jian‐Zhong; Hu, Shen‐Jiang

doi:10.1038/s41598-018-32836-x

Cited by 7 publications

(7 citation statements)

References 42 publications

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confidence: 58%

“…In all such cases, sex hormones act in concert with these EPHs/EFNs to control BP. Some of the findings from the mouse model have been corroborated by human genetic studies, in which we revealed that some variants in the EFNB2, EFNB3, and EPHA4 genes or a related signaling molecule gene are significantly associated with hypertension in a sex-specific way (19,21,22,24,25).EPHB6 is highly expressed in the medullae of adrenal glands, which are the major source of catecholamine (CAT) in the circulation. The ambient blood CAT level reflects this hormone's effect on the homeostasis of BP (26,27).…”

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confidence: 59%

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EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells

Shi

Wang

Peng

et al. 2019

Journal of Biological Chemistry

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Edited by John M. Denu EPHB6 is a member of the erythropoietin-producing hepatocellular kinase (EPH) family and a receptor tyrosine kinase with a dead kinase domain. It is involved in blood pressure regulation and adrenal gland catecholamine (CAT) secretion, but several facets of EPHB6-mediated CAT regulation are unclear. In this study, using biochemical, quantitative RT-PCR, immunoblotting, and gene microarray assays, we found that EPHB6 up-regulates CAT biosynthesis in adrenal gland chromaffin cells (AGCCs). We observed that epinephrine content is reduced in the AGCCs from male Ephb6-KO mice, caused by decreased expression of tyrosine hydroxylase, the rate-limiting enzyme in CAT biosynthesis. We demonstrate that the signaling pathway from EPHB6 to tyrosine hydroxylase expression in AGCCs involves Rac family small GTPase 1 (RAC1), MAP kinase kinase 7 (MKK7), c-Jun N-terminal kinase (JNK), proto-oncogene c-Jun, activator protein 1 (AP1), and early growth response 1 (EGR1). On the other hand, signaling via extracellular signalregulated kinase (ERK1/2), p38 mitogen-activated protein kinase, and ELK1, ETS transcription factor (ELK1) was not affected by EPHB6 deletion. We further report that EPHB6's effect on AGCCs was via reverse signaling through ephrin B1 and that EPHB6 acted in concert with the nongenomic effect of testosterone to control CAT biosynthesis. Our findings elucidate the mechanisms by which EPHB6 modulates CAT biosynthesis and identify potential therapeutic targets for diseases, such as hypertension, caused by dysfunctional CAT biosynthesis.EPHB6 is a member of erythropoietin-producing hepatocellular kinases (EPHs), 3 the largest family of receptor tyrosine kinases (1, 2). The ligands of EPH are called ephrins (EFNs), which are also membrane proteins. EFNs can trigger EPH signaling by canonical forward signaling, i.e. from ligand EFNs to receptor EPHs. However, EFNs can also receive signaling from EPHs and transduce signals into cells, and such noncanonical action (i.e. from EPHs to EFNs) is called reverse signaling (2). The interaction between EPHs and EFNs is promiscuous; one EPH can bind to multiple EFNs and one EFN to multiple EPHs. In general, EPHA family members bind to EFNAs, and EPHB family members binds to EFNBs (2).EPHs/EFNs function in many organs and systems (2). We first reported the critical involvement of EPHs and EFNs in the immune system (3-15). In the past 5 years, we have demonstrated in a series of publications (16 -25) that EPHs/EFNs are involved in regulating blood pressure (BP), which was previously unknown. We reported, using gene knockout mouse models, that although EPHB6, EFNB1, EFNB3, and EPHA4 deletion results in BP elevation (16,17,20,25), EPHB4 and EFNB2 deletion lowers it (18,19). Thus, members of EPHBs/ EFNBs are a novel yin and yang system that fine-tunes BP homeostasis. In all such cases, sex hormones act in concert with these EPHs/EFNs to control BP. Some of the findings from the mouse model have been corroborated by human genetic studies, in which we revealed that s...

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confidence: 58%

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confidence: 59%

EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells

Shi

Wang

Peng

et al. 2019

Journal of Biological Chemistry

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“…CCL20 [188], CRH (corticotropin releasing hormone) [189], SPP1 [190], LDLR (low density lipoprotein receptor) [191], RORA (RAR related orphan receptor A) [192], LYZ (lysozyme) [193], PTPRN2 [194], DAPK2 [195], OIP5 [196], PON3 [197], NR4A3 [198], VCAN (versican) [199], CNTNAP2 [200], IL1RAP [201], GLI2 [202], CDH13 [203], AEBP1 [204], BGN (biglycan) [205], LOX (lysyl oxidase) [206], IL1RL1 [207] and LUM (lumican) [208] were found to be involved in advancement of obesity, but these genes might be key for development of T2DM. C4BPA [209], KYNU (kynureninase) [210], ORM1 [211], ARSA (arylsulfatase A) [212], CYB5R3 [213], MAT1A [214], SDC4 [215], ASL (argininosuccinate lyase) [216], SLC4A4 [217], EPHB6 [218], SPARCL1 [219], THBS2 [220], EFNB2 [221] and CD248 [222] were revealed to be associated with hypertension, but these genes might be involved in progression of T2DM. GSDMD (gasdermin D) [223], UNC5B [224] and PDGFB (platelet derived growth factor subunit B) [225] have been reported significantly expressed in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

Vastrad¹,

Vastrad²

2021

Preprint

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Type 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real time polymerase chain reaction (RT PCR). In total, 925 DEGs were identified in T2DM, including 447 up regulated genes and 478 down-regulated genes. Functional enrichment analysis results showed that up regulated DEGs were significantly enriched in defense response, neutrophil degranulation, cell adhesion and extracellular matrix organization. The top 10 hub genes, JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 were identified from the PPI network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network. Furthermore, ROC analysis and RT PCR revealed that JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 might serve as biomarkers in T2DM. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of T2DM. The identified hub genes may participate in the onset and advancement of T2DM and serve as therapeutic targets.

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“…The details of the patient population were previously described (Wu et al, 2018) but are presented here again for the convenience of readers. A total of 4,480 male patients ≥40 years old from the Cardiology Ward, Endocrinology Ward, and Physical Examination Center of First Affiliated Hospital, College of Medicine, Zhejiang University in Hangzhou, China, were recruited for this study.…”

Section: Patient Populationmentioning

confidence: 99%

A Variant in the Nicotinic Acetylcholine Receptor Alpha 3 Subunit Gene Is Associated With Hypertension Risks in Hypogonadic Patients

Wang

Shi

et al. 2020

Front. Genet.

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Ephb6 gene knockout causes hypertension in castrated mice. EPHB6 controls catecholamine secretion by adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent way. Nicotinic acetylcholine receptor (nAChR) is a ligand-gated Ca2+/Na+ channel, and its opening is the first signaling event leading to catecholamine secretion by AGCCs. There is a possibility that nAChR might be involved in EPHB6 signaling, and thus sequence variants of its subunit genes are associated with hypertension risks. CHRNA3 is the major subunit of nAChR used in human and mouse AGCCs. We conducted a human genetic study to assess the association of CHRNA3 variants with hypertension risks in hypogonadic males. The study cohort included 1,500 hypogonadic Chinese males with (750 patients) or without (750 patients) hypertension. The result revealed that SNV rs3743076 in the fourth intron of CHRNA3 was significantly associated with hypertension risks in the hypogonadic males. We further showed that EPHB6 physically interacted with CHRNA3 in AGCCs, providing a molecular basis for nAChR being in the EPHB6 signaling pathway.

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Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism

Cited by 7 publications

References 42 publications

EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells

EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

A Variant in the Nicotinic Acetylcholine Receptor Alpha 3 Subunit Gene Is Associated With Hypertension Risks in Hypogonadic Patients

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