Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease

Liu, Shiming; Su, Zhaobing; Tan, Sainan; Ni, Bin; Pan, Hong; Liu, Beihong; Wang, Jing; Xiao, Jing; Chen, Qiuhong

doi:10.1007/s00246-017-1649-y

Cited by 13 publications

(11 citation statements)

References 19 publications

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“…Non-synonymous and synonymous variants in CITED2 sequence or reduced expression of CITED2 have been associated with CHD worldwide [25,26,39,[147][148][149][150]. Ventricular (VSD) and atrial (ASD) septal defects, transposition of the great arteries (TGA) and the tetralogy of Fallot (TOF) are the most frequent heart anomalies associated with CITED2 variants Regenerative Medicine Frontiers…”

Section: Cited Congenital Heart Disease and Adult Heart Functionmentioning

confidence: 99%

“…https://doi.org/10.20900/rmf20190005 ( Figure 3). Most of CITED2 variants identified in patients with CHD, only marginally affect its capacity to repress the transcriptional activity of HIF-1ɑ and/or to co-activate TFAP2 ex vivo [25,26,39,[147][148][149][150]. However, CITED2 mutations in patients may result in severe impairment of VEGF and PITX2C gene expression, which are necessary for normal development of the vasculature and left-right patterning, respectively [26].…”

Section: Of 27mentioning

confidence: 99%

“…Percentages of defects related to left-right patterning defects are also indicated in the grey insert. Metanalysis of data published elsewhere[25,26,39,[147][148][149][150].In adult hearts, CITED1 has not been detected, while CITED2 andCITED4 are expressed. However, their contribution to heart homeostasis or pathological processes remains largely unclear.…”

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confidence: 95%

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CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

2019

Regen Med Front.

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The CITED family of transcriptional modulators plays multiple roles in the development of vertebrates. These proteins are characterized by the conservation of a carboxy-terminal domain which defines this family and has a high affinity for the transcriptional co-activators CBP/p300. In humans, mutations in some CITED genes or deregulation of their expression are associated with developmental anomalies. In particular, CITED2 dysfunction has been associated with congenital heart disease.Although most studies have reported the critical function of CITED proteins during development, there is increasing evidence supporting an important role for these proteins in physiological functions of adult organisms and pathologies such as cardiomyopathies and cancer. In addition, recent studies have pointed out the involvement of CITED proteins in embryonic and adult stem cells self-renewal, and cell fate decisions. Here, we present an overview of the CITED transcriptional modulators, their protein interactors and gene networks, with an emphasis on their importance in pluripotent stem cells and cardiogenesis.

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Section: Cited Congenital Heart Disease and Adult Heart Functionmentioning

confidence: 99%

Section: Of 27mentioning

confidence: 99%

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CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

2019

Regen Med Front.

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“…Several studies have demonstrated that CITED2 prevents the activation of pro-angiogenic genes such as VEGF and inhibits angiogenesis by competing with HIF-1α to bind to CBP/P300 [32][33][34]. CITED2 is also known to act as a negative regulator of fracture healing, and its expression is inversely related to the expression of VEGF and HIF-1α genes [35][36][37][38]. The expression of CITED2 is up-regulated in vascular endothelial cells of diabetic patients, while over-expressed CITED2 inhibits transcriptional activation of HIF-1α and ultimately leads to angiogenesis disorders [39].…”

Section: Introductionmentioning

confidence: 99%

Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway

Xiao

Zhang

Liu

et al. 2020

Aging

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Despite being an attractive cell type for mesenchymal stem cell (MSC) transplantation therapy for wound healing, human adipose-derived stem cells (hADSCs) from diabetes mellitus (DM) patients result in remarkable retention of stem cell activity due to diabetes-induced glucolipotoxicity. We explored the effect of diabetes and medium containing AGEs on the cell activity, phenotype, multipotency, angiogenic potential, and the therapeutic effect of hADSCs. Then, miRNA-1248 was selected by miRNA microarray analysis to further study the core molecular pathways that regulate the wound healing ability of hADSCs. hADSCs isolated from DM patients or cultured in medium containing AGEs in vitro exhibited decreased effectiveness in stem cell therapy. The expression of miRNA-1248 was decreased in the hADSCs of DM patients and hence failed to positively regulate stem cell activity, differentiation functions, and angiogenesis promotion effect. This concomitantly increased the expression of CITED2, an inhibitor of HIF-1α, thus influencing growth factors that promote angiogenesis, cellular proliferation, and wound healing. Overall, our data demonstrated that the glucolipotoxicity-impaired wound healing ability of hADSCs might occur through the miR-1248/CITED2/HIF-1α pathway. MiRNA-1248 may have potential to be used as a novel therapeutic target for wound healing in DM patients or restoring the wound healing ability of diabetic hADSCs.

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“…Knock-out experiments of CITED2 in mice may result in several cardiac defects. In a study involving 187 unrelated Tibetans with CHD, Liu et al found a novel mutation of CITED2 that enhanced the expression of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia-inducible factor 1 alpha (HIF-1α) [10]. In this journal, in a recent issue, Pan et al studied the endothelial PAS domain-containing gene 1 (EPAS1) in CHD in Tibetans [11].…”

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confidence: 99%

EPAS 1, congenital heart disease, and high altitude: disclosures by genetics, bioinformatics, and experimental embryology

Sergi

2019

Bioscience Reports

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The high-altitude environment is a challenge for human settlement. Low oxygen concentrations, extreme cold, and a harsh arid climate are doubtlessly challenges for the colonization of the Tibetan plateau. I am delighted to comment on the article of Pan et al. (2018) on mutations in endothelial PAS domain-containing protein 1 (EPAS1) in congenital heart disease in Tibetans. In humans, the EPAS1 gene is responsible for coding EPAS1 protein, an alias of which is HIF2α, an acronym for hypoxia-inducible factor 2 alpha. EPAS1 is a type of hypoxia-inducible factors, which are collected as a group of transcription factors involved in body response to oxygen level. EPAS1 gene is active under hypoxic conditions and plays an essential role in the development of the heart and in the management of the catecholamine balance, mutations of which have been identified in neuroendocrine tumors. In this article, Pan et al. investigated Tibetan patients with and without non-syndromic congenital heart disease. They identified two novel EPAS1 gene mutations, of which N203H mutation significantly affected the transcription activity of the vascular endothelial growth factor (VEGF) promoter, particularly in situations of hypoxia. VEGF is a downstream target of HIF-2 (other than HIF-1), and the expression levels of either HIF-1α or HIF-2α correlate positively to VEGF expression. Pan et al.’s data may be of incitement to further evaluate protein–protein interaction and using experimental animal models. Moreover, it may also be a stimulus for setting up genetic epidemiologic studies for other populations living at high altitudes.

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Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease

Cited by 13 publications

References 19 publications

CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

CITED Proteins in the Heart of Pluripotent Cells and in Heart’s Full Potential

Diabetes-induced glucolipotoxicity impairs wound healing ability of adipose-derived stem cells-through the miR-1248/CITED2/HIF-1α pathway

EPAS 1, congenital heart disease, and high altitude: disclosures by genetics, bioinformatics, and experimental embryology

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