Involvement of AP-1 and C/EBPβ in Upregulation of Endothelin B (ETB) Receptor Expression in a Rodent Model of Glaucoma

He, Shuning; Minton, Alena Z.; Ying, Hai; Stankowska, Dorota; Sun, Xiangle; Krishnamoorthy, Raghu R

doi:10.1371/journal.pone.0079183

Cited by 20 publications

(32 citation statements)

References 53 publications

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“…1 A and B), where the underlying transcription factors were reported to have roles in endothelin-mediated cardiac function (16,18,19). Promoter luciferase assay of the EDNRB gene indicated an 89-fold increased activity with an intact 1,258-bp promoter sequence and a further boost of 2.7-and 3.1-fold with overexpression of c-Jun or C/EBPb, respectively (21). Additionally, the promoter region was also found to be rich in CpG dinucleotide repeats, and methylation of this CpG-riched region reportedly regulates EDNRB gene expression (25).…”

Section: Discussionmentioning

confidence: 98%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB −/+ heterozygote mice are treated with lower levels of oxygen (O 2 ), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O 2 ) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O 2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB −/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB −/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB −/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.is often referred to as a biosignature, a chemical marker in the atmosphere closely associated with life, and in a complex organism, such as humans, various physiological systems have evolved to maintain an optimal O 2 homeostasis. Arguably, humans living at high altitude (HA) for thousands of years ought to have undergone a significant level of natural selection to adjust to the challenging hypoxic condition. Human adaptation to HA hypoxia, which can be protective to tissues, can potentially be harnessed for better therapeutic modalities for sea-level diseases that involve hypoxia and ischemia in their pathogenesis. Indeed, lessons from such an "experiment in nature" can be derived from HA adaptation and can advance lowaltitude medicine (1). With the advent of newer technology including next-generation sequencing (seq), this idea has recently led to intensive efforts, and a number of publications have appeared on studies of human populations living at HA (2-4). These studies also draw added significance not only to sea-level human diseases but also to more than 140 million people living at an altitude above 2,500 m, where the hypoxic condition presents a major challenge for survival (5). Although a number of laboratory methods that mimic hypoxia adaptation using model organisms (6) have been used as tools to identify causative genetic pathways (7,8), studies in human populations living at different H...

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Section: Discussionmentioning

confidence: 98%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The most strongly associated pathways with this gene set appeared to fall within a wider theme of cell-cycle regulation, with “IL6-mediated signaling events,” “Oncostatin M Signaling Pathway,” “Cellular Senescence,” and “Apoptosis Modulation and Signaling” (Table 3). Many of the genes involved in these pathways, like JUN, FOS, CDKN2A , and TP53 , were upregulated in experimental rodent models of glaucoma (induced OHT, optic nerve transection), and likely contribute to glaucoma’s characteristic optic nerve atrophy by inducing apoptosis in RGCs or the supporting retinal glia (He et al, 2013; Yang et al, 2007). …”

Section: Pathway Analysis and Functional Annotationmentioning

confidence: 99%

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Danford

Verkuil

Choi

et al. 2017

Progress in Retinal and Eye Research

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Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the “POAGome.” We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

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“…ETs contribute to the pathogenesis of various retinopathies like glaucoma and diabetic retinopathy [24,27]. The expression of retinal ETs, and of ET A and ET B receptors, is upregulated in experimental diabetic retinopathy and glaucoma [9,16]. ET-1 and ET-2 are potent vasoconstrictors; vasoconstriction may produce retinal ischemia [5].…”

Section: Animals and Experimental Diabetesmentioning

confidence: 99%

Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling

et al. 2016

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Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Here, we show that endothelin-1 (ET-1) dose-dependently inhibits the hypoosmotic swelling of Müller cells in freshly isolated retinal slices of control and diabetic rats, with a maximal inhibition at 100 nM. Osmotic Müller cell swelling was also inhibited by ET-2. The effect of ET-1 was mediated by activation of ET and ET receptors resulting in transactivation of metabotropic glutamate receptors, purinergic P2Y, and adenosine A receptors. ET-1 (but not ET-2) also inhibited the osmotic swelling of bipolar cells in retinal slices, but failed to inhibit the swelling of freshly isolated bipolar cells. The inhibitory effect of ET-1 on the bipolar cell swelling in retinal slices was abrogated by inhibitors of the FGF receptor kinase (PD173074) and of TGF-β1 superfamily activin receptor-like kinase receptors (SB431542), respectively. Both Müller and bipolar cells displayed immunoreactivities of ET and ET receptor proteins. The data may suggest that neuroprotective effects of ETs in the retina are in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. ET-1 acts directly on Müller cells, while the inhibitory effect of ET-1 on bipolar cell swelling is indirectly mediated, via stimulation of the release of growth factors like bFGF and TGF-β1 from Müller cells.

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Involvement of AP-1 and C/EBPβ in Upregulation of Endothelin B (ETB) Receptor Expression in a Rodent Model of Glaucoma

Cited by 20 publications

References 53 publications

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling

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