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Chin CH, Chien CC, Huang CJ, Ke CY, Lee YJ. Differential Transcription Factor Activator Protein-2 Delta Genotypes Affect the Levels of Interleukin-1 Beta, Interleukin 8, and Vascular Endothelial Growth Factor-C in the Retinal Pigment Epithelial Cells after Long-term Light Exposure. JOURNAL OF PHYSIOLOGICAL INVESTIGATION 2025:02275668-990000000-00037. [PMID: 40396232 DOI: 10.4103/ejpi.ejpi-d-24-00107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 03/26/2025] [Indexed: 05/22/2025]
Abstract
ABSTRACT Retinal degeneration accompanied by abnormal neovascularization from the choroid in the macular area is a critical disease to cure. Retinal cell apoptosis or inflammation in the macula can lead to neovascularization in that area. Some environmental factors such as long-term light exposure, particularly the blue end of the light spectrum, can damage the retina, causing such a disease. Improved understanding of genetic molecules has indicated that certain genes may be potential biomarkers of neovascular macular degeneration. This study aimed to investigate the expression of transcription factor activator protein-2 δ (TFAP-2D) in the retina and explore its role in the pathogenesis of retinal degeneration. For this, a long-term light exposure animal model was used to evaluate TFAP-2D expression in the retina. In addition, two vectors overexpressing different genotypes of TFAP-2D were transfected into retinal pigment epithelial (RPE) cells, and the expression of angiogenesis molecules was investigated. It was found that TFAP-2D expression was observed in the RPE area of the retina in long-term light-exposed rats; however, no TFAP-2D expression was detected in the retina of control (normal) rats. Interleukins (ILs) 1B, IL8, vascular endothelial growth factor (VEGF)-C, and one VEGF receptor (kinase insert domain receptor) were significantly upregulated in RPE cells with TFAP-2D with a C allele at rs78648104 (TFAP-2D-C) overexpression. In conclusion, experiments with different TFAP-2D genotypes revealed that long-term light exposure upregulated TFAP-2D expression in the RPE cells of the retina. In addition, overexpression of TFAP-2D-C induced the release of IL1B, IL8, and VEGF-C, which may lead to neovascularization in the choroid and retina.
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Affiliation(s)
- Chih-Hui Chin
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Cardiovascular Center, Cathay General Hospital, Taipei, Taiwan
| | - Chih-Cheng Chien
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Chi-Jung Huang
- Department of Medical Research, Cathay General Hospital, Taipei, Taiwan
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Ying Ke
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Yih-Jing Lee
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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Kuna M, Soares MJ. Cited2 is a key regulator of placental development and plasticity. Bioessays 2024; 46:e2300118. [PMID: 38922923 PMCID: PMC11331489 DOI: 10.1002/bies.202300118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
The biology of trophoblast cell lineage development and placentation is characterized by the involvement of several known transcription factors. Central to the action of a subset of these transcriptional regulators is CBP-p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). CITED2 acts as a coregulator modulating transcription factor activities and affecting placental development and adaptations to physiological stressors. These actions of CITED2 on the trophoblast cell lineage and placentation are conserved across the mouse, rat, and human. Thus, aspects of CITED2 biology in hemochorial placentation can be effectively modeled in the mouse and rat. In this review, we present information on the conserved role of CITED2 in the biology of placentation and discuss the use of CITED2 as a tool to discover new insights into regulatory mechanisms controlling placental development.
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Affiliation(s)
- Marija Kuna
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS
- Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Michael J. Soares
- Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, KS
- Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS
- Center for Perinatal Research, Children’s Mercy Research Institute, Children’s Mercy, Kansas City, MO
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Bragança J, Pinto R, Silva B, Marques N, Leitão HS, Fernandes MT. Charting the Path: Navigating Embryonic Development to Potentially Safeguard against Congenital Heart Defects. J Pers Med 2023; 13:1263. [PMID: 37623513 PMCID: PMC10455635 DOI: 10.3390/jpm13081263] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/26/2023] Open
Abstract
Congenital heart diseases (CHDs) are structural or functional defects present at birth due to improper heart development. Current therapeutic approaches to treating severe CHDs are primarily palliative surgical interventions during the peri- or prenatal stages, when the heart has fully developed from faulty embryogenesis. However, earlier interventions during embryonic development have the potential for better outcomes, as demonstrated by fetal cardiac interventions performed in utero, which have shown improved neonatal and prenatal survival rates, as well as reduced lifelong morbidity. Extensive research on heart development has identified key steps, cellular players, and the intricate network of signaling pathways and transcription factors governing cardiogenesis. Additionally, some reports have indicated that certain adverse genetic and environmental conditions leading to heart malformations and embryonic death may be amendable through the activation of alternative mechanisms. This review first highlights key molecular and cellular processes involved in heart development. Subsequently, it explores the potential for future therapeutic strategies, targeting early embryonic stages, to prevent CHDs, through the delivery of biomolecules or exosomes to compensate for faulty cardiogenic mechanisms. Implementing such non-surgical interventions during early gestation may offer a prophylactic approach toward reducing the occurrence and severity of CHDs.
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Affiliation(s)
- José Bragança
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal
| | - Rute Pinto
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Bárbara Silva
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- PhD Program in Biomedical Sciences, Faculty of Medicine and Biomedical Sciences, Universidade do Algarve, 8005-139 Faro, Portugal
| | - Nuno Marques
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Helena S. Leitão
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
| | - Mónica T. Fernandes
- Algarve Biomedical Center-Research Institute (ABC-RI), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- Algarve Biomedical Center (ABC), University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
- School of Health, University of Algarve Campus Gambelas, 8005-139 Faro, Portugal
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Lu M, Liu Y, Xian Z, Yu X, Chen J, Tan S, Zhang P, Guo Y. VEGF to CITED2 ratio predicts the collateral circulation of acute ischemic stroke. Front Neurol 2022; 13:1000992. [PMID: 36247751 PMCID: PMC9563238 DOI: 10.3389/fneur.2022.1000992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/24/2022] [Indexed: 11/30/2022] Open
Abstract
Objective The research objective was to evaluate the predicting role of the vascular endothelial growth factor to CBP/P300-interacting transactivator with Glu/Asp-rich C-terminal domain 2 Ratio (VEGF/CITED2) from peripheral blood mononuclear cells (PBMCs) in the collateral circulation of acute ischemic stroke (AIS). Methods In an observational study of patients with AIS, the western blot was applied to test the protein expression of VEGF and CITED2. Then, we calculated the VEGF/CITED2 and collected other clinical data. Binary logistic regression analysis between collateral circulation and clinical data was performed. Finally, receiver operating characteristic (ROC) curve analysis was used to explore the predictive value of VEGF/CITED2. Results A total of 67 patients with AIS were included in the study. Binary logistic regression analysis indicated the VEGF/CITED2 (OR 165.79, 95%CI 7.25–3,791.54, P = 0.001) was an independent protective factor. The ROC analyses showed an area under the ROC curve of the VEGF/CITED2 was 0.861 (95%CI 0.761–0.961). The optimal cutoff value of 1.013 for VEGF/CITED2 had a sensitivity of 89.1% and a specificity of 85.7%. Conclusion In patients with AIS, the VEGF/CITED2 was related to the establishment of collateral circulation. The VEGF/CITED2 is a potentially valuable biomarker for predicting collateral circulation. Clinical trial registration ClinicalTrials.gov, identifier: NCT05345366.
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Affiliation(s)
- Minyi Lu
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuben Liu
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiqiang Xian
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyao Yu
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Chen
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng Tan
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peidong Zhang
- Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- *Correspondence: Peidong Zhang
| | - Yang Guo
- Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Yang Guo
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Chen Z, Chen HX, Hou HT, Yin XY, Yang Q, Han J, He GW. Genetic Variants of CITED2 Gene Promoter in Human Atrial Septal Defects: Case-Control Study and Cellular Functional Verification. J Cardiovasc Dev Dis 2022; 9:321. [PMID: 36286273 PMCID: PMC9604052 DOI: 10.3390/jcdd9100321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 11/16/2022] Open
Abstract
Atrial septal defect (ASD) is one of the most common forms of congenital heart disease (CHD). Genetic variants in the coding region of the CITED2 gene are known to be significantly correlated with CHD, but the role of variants in the promoter region of CITED2 is unknown. We investigated variants in the promoter of the CITED2 gene in 625 subjects (332 ASD and 293 healthy controls) through Sanger sequencing. Four variants in the CITED2 gene promoter were found only in eight ASD patients with zero occurrence in the control subjects (one case of g.4078A>C(rs1165649373), one case of g.4240C>A(rs1235857801), four cases of g.4935C>T(rs111470468), two cases of g.5027C>T(rs112831934)). Cellular functional analysis showed that these four variants significantly changed the transcriptional activity of the CITED2 gene promoter in HEK-293 and HL-1 cells. Electrophoretic mobility change assay results and JASPAR database analysis demonstrated that these variants created or destroyed a series of possible transcription factor binding sites, resulting in changes in the expression of CITED2 protein. We conclude that the variants of CITED2 promoter in ASD patients affect the transcriptional activity and are likely involved in the occurrence and development of ASD. These findings provide new perspectives on the pathogenesis and potential therapeutic insights of ASD.
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Affiliation(s)
- Zhuo Chen
- School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China and The Institute of Cardiovascular Diseases, TEDA International Cardiovascular Hospital, Tianjin University & Chinese Academy of Medical Sciences, Tianjin 300457, China
| | - Huan-Xin Chen
- The Institute of Cardiovascular Diseases and Department Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University and Chinese Academy of Medical Sciences, Tianjin 300457, China
| | - Hai-Tao Hou
- The Institute of Cardiovascular Diseases and Department Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University and Chinese Academy of Medical Sciences, Tianjin 300457, China
| | - Xiu-Yun Yin
- School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China and The Institute of Cardiovascular Diseases, TEDA International Cardiovascular Hospital, Tianjin University & Chinese Academy of Medical Sciences, Tianjin 300457, China
| | - Qin Yang
- The Institute of Cardiovascular Diseases and Department Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University and Chinese Academy of Medical Sciences, Tianjin 300457, China
| | - Jun Han
- School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China
| | - Guo-Wei He
- School of Pharmacy, Drug Research & Development Center, Wannan Medical College, Wuhu, Anhui 241002, China and The Institute of Cardiovascular Diseases, TEDA International Cardiovascular Hospital, Tianjin University & Chinese Academy of Medical Sciences, Tianjin 300457, China
- The Institute of Cardiovascular Diseases and Department Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Tianjin University and Chinese Academy of Medical Sciences, Tianjin 300457, China
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Liu Y, Zhang Q, Yang L, Tian W, Yang Y, Xie Y, Li J, Yang L, Gao Y, Xu Y, Liu J, Wang Y, Yan J, Li G, Shen Y, Qi Z. Metformin Attenuates Cardiac Hypertrophy Via the HIF-1α/PPAR-γ Signaling Pathway in High-Fat Diet Rats. Front Pharmacol 2022; 13:919202. [PMID: 35833024 PMCID: PMC9271627 DOI: 10.3389/fphar.2022.919202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/11/2022] [Indexed: 12/19/2022] Open
Abstract
Coronary artery disease (CAD) and cardiac hypertrophy (CH) are two main causes of ischemic heart disease. Acute CAD may lead to left ventricular hypertrophy (LVH). Long-term and sustained CH is harmful and can gradually develop into cardiac insufficiency and heart failure. It is known that metformin (Met) can alleviate CH; however, the molecular mechanism is not fully understood. Herein, we used high-fat diet (HFD) rats and H9c2 cells to induce CH and clarify the potential mechanism of Met on CH. We found that Met treatment significantly decreased the cardiomyocyte size, reduced lactate dehydrogenase (LDH) release, and downregulated the expressions of hypertrophy markers ANP, VEGF-A, and GLUT1 either in vivo or in vitro. Meanwhile, the protein levels of HIF-1α and PPAR-γ were both decreased after Met treatment, and administrations of their agonists, deferoxamine (DFO) or rosiglitazone (Ros), markedly abolished the protective effect of Met on CH. In addition, DFO treatment upregulated the expression of PPAR-γ, whereas Ros treatment did not affect the expression of HIF-1α. In conclusion, Met attenuates CH via the HIF-1α/PPAR-γ signaling pathway.
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Affiliation(s)
- Yuansheng Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Qian Zhang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Lei Yang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
- Tianjin Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Tianjin, China
| | - Wencong Tian
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Yinan Yang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
- Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
| | - Yuhang Xie
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Jing Li
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Liang Yang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Yang Gao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Yang Xu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Jie Liu
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Yachen Wang
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Jie Yan
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Guoxun Li
- Xinjiang Production and Construction Corps Hospital, Urumqi, China
- Tianjin Union Medical Center, Tianjin, China
- *Correspondence: Guoxun Li, ; Yanna Shen, ; Zhi Qi,
| | - Yanna Shen
- Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, Tianjin, China
- *Correspondence: Guoxun Li, ; Yanna Shen, ; Zhi Qi,
| | - Zhi Qi
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
- Xinjiang Production and Construction Corps Hospital, Urumqi, China
- Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, China
- *Correspondence: Guoxun Li, ; Yanna Shen, ; Zhi Qi,
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Abstract
Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) is a transcription co-factor that interacts with several other transcription factors and co-factors, and serves critical roles in fundamental cell processes, including proliferation, apoptosis, differentiation, migration and autophagy. The interacting transcription factors or co-factors of CITED2 include LIM homeobox 2, transcription factor AP-2, SMAD2/3, peroxisome proliferator-activated receptor γ, oestrogen receptor, MYC, Nucleolin and p300/CBP, which regulate downstream gene expression, and serve important roles in the aforementioned fundamental cell processes. Emerging evidence has demonstrated that CITED2 serves an essential role in embryonic and adult tissue stem cells, including hematopoietic stem cells and tendon-derived stem/progenitor cells. Additionally, CITED2 has been reported to function in different types of cancer. Although the functions of CITED2 in different tissues vary depending on the interaction partner, altered CITED2 expression or altered interactions with transcription factors or co-factors result in alterations of fundamental cell processes, and may affect stem cell maintenance or cancer cell survival. The aim of this review is to summarize the molecular mechanisms of CITED2 function and how it serves a role in stem cells and different types of cancer based on the currently available literature.
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Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol 2020; 11:260-274. [PMID: 32728529 PMCID: PMC7360518 DOI: 10.5306/wjco.v11.i5.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.
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Affiliation(s)
- Mónica T Fernandes
- School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Sofia M Calado
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Leonardo Mendes-Silva
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| | - José Bragança
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
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Santos JMA, Mendes-Silva L, Afonso V, Martins G, Machado RSR, Lopes JA, Cancela L, Futschik ME, Sachinidis A, Gavaia P, Bragança J. Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants. Cell Death Dis 2019; 10:582. [PMID: 31378782 PMCID: PMC6680046 DOI: 10.1038/s41419-019-1816-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/06/2019] [Accepted: 07/11/2019] [Indexed: 02/07/2023]
Abstract
Mutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.
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Affiliation(s)
- João M A Santos
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
| | - Leonardo Mendes-Silva
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
| | - Vanessa Afonso
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
| | - Gil Martins
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139, Faro, Portugal
| | - Rui S R Machado
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
| | - João A Lopes
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
| | - Leonor Cancela
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139, Faro, Portugal
- ABC-Algarve Biomedical Centre, 8005-139, Faro, Portugal
| | - Matthias E Futschik
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139, Faro, Portugal
- School of Biomedical Sciences, Faculty of Medicine and Dentistry, Institute of Translational and Stratified Medicine (ITSMED), University of Plymouth, Plymouth, PL6 8BU, UK
| | - Agapios Sachinidis
- Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany
| | - Paulo Gavaia
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139, Faro, Portugal
| | - José Bragança
- Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139, Faro, Portugal.
- Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal.
- ABC-Algarve Biomedical Centre, 8005-139, Faro, Portugal.
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Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity. Arterioscler Thromb Vasc Biol 2019; 39:1113-1124. [DOI: 10.1161/atvbaha.119.312665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Objective—
To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization.
Approach and Results—
Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2 (extracellular signal-regulated kinases 1/2). TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK (phospho Thr202/Tyr204 ERK1/2) and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis.
Conclusions—
TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis.
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11
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Courtney JA, Cnota JF, Jones HN. The Role of Abnormal Placentation in Congenital Heart Disease; Cause, Correlate, or Consequence? Front Physiol 2018; 9:1045. [PMID: 30131711 PMCID: PMC6091057 DOI: 10.3389/fphys.2018.01045] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/13/2018] [Indexed: 01/11/2023] Open
Abstract
Congenital heart disease (CHD) is the most common birth defect, affecting ~1% of all live births (van der Linde et al., 2011). Despite improvements in clinical care, it is the leading cause of infant mortality related to birth defects (Yang et al., 2006) and burdens survivors with significant morbidity (Gilboa et al., 2016). Furthermore, CHD accounts for the largest proportion (26.7%) of birth defect-associated hospitalization costs—up to $6.1 billion in 2013 (Arth et al., 2017). Yet after decades of research with a primary focus on genetic etiology, the underlying cause of these defects remains unknown in the majority of cases (Zaidi and Brueckner, 2017). Unexplained CHD may be secondary to undiscovered roles of noncoding genetic, epigenetic, and environmental factors, among others (Russell et al., 2018). Population studies have recently demonstrated that pregnancies complicated by CHD also carry a higher risk of developing pathologies associated with an abnormal placenta including growth disturbances (Puri et al., 2017), preeclampsia (Auger et al., 2015; Brodwall et al., 2016), preterm birth (Laas et al., 2012), and stillbirth (Jorgensen et al., 2014). Both the heart and placenta are vascular organs and develop concurrently; therefore, shared pathways almost certainly direct the development of both. The involvement of placental abnormalities in congenital heart disease, whether causal, commensurate or reactive, is under investigated and given the common developmental window and shared developmental pathways of the heart and placenta and concurrent vasculature development, we propose that further investigation combining clinical data, in vitro, in vivo, and computer modeling is fundamental to our understanding and the potential to develop therapeutics.
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Affiliation(s)
- Jennifer A Courtney
- Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Division of General Pediatric and Thoracic Surgery, Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - James F Cnota
- Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Helen N Jones
- Division of General Pediatric and Thoracic Surgery, Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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12
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Thomford NE, Dzobo K, Yao NA, Chimusa E, Evans J, Okai E, Kruszka P, Muenke M, Awandare G, Wonkam A, Dandara C. Genomics and Epigenomics of Congenital Heart Defects: Expert Review and Lessons Learned in Africa. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2018; 22:301-321. [PMID: 29762087 PMCID: PMC6016577 DOI: 10.1089/omi.2018.0033] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Congenital heart defects (CHD) are structural malformations found at birth with a prevalence of 1%. The clinical trajectory of CHD is highly variable and thus in need of robust diagnostics and therapeutics. Major surgical interventions are often required for most CHDs. In Africa, despite advances in life sciences infrastructure and improving education of medical scholars, the limited clinical data suggest that CHD detection and correction are still not at par with the rest of the world. But the toll and genetics of CHDs in Africa has seldom been systematically investigated. We present an expert review on CHD with lessons learned on Africa. We found variable CHD phenotype prevalence in Africa across countries and populations. There are important gaps and paucity in genomic studies of CHD in African populations. Among the available genomic studies, the key findings in Africa were variants in GATA4 (P193H), MTHFR 677TT, and MTHFR 1298CC that were associated with atrial septal defect, ventricular septal defect (VSD), Tetralogy of Fallot (TOF), and patent ductus arteriosus phenotypes and 22q.11 deletion, which is associated with TOF. There were no data on epigenomic association of CHD in Africa, however, other studies have shown an altered expression of miR-421 and miR-1233-3p to be associated with TOF and hypermethylation of CpG islands in the promoter of SCO2 gene also been associated with TOF and VSD in children with non-syndromic CHD. These findings signal the urgent need to develop and implement genetic and genomic research on CHD to identify the hereditary and genome-environment interactions contributing to CHD. These projected studies would also offer comparisons on CHD pathophysiology between African and other populations worldwide. Genomic research on CHD in Africa should be developed in parallel with next generation technology policy research and responsible innovation frameworks that examine the social and political factors that shape the emergence and societal embedding of new technologies.
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Affiliation(s)
- Nicholas Ekow Thomford
- 1 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
- 2 School of Medical Sciences, University of Cape Coast , Cape Coast, Ghana
| | - Kevin Dzobo
- 3 ICGEB, Cape Town Component, University of Cape Town , Cape Town, South Africa
- 4 Division of Medical Biochemistry, IIDMM, Department of IBM, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa
| | - Nana Akyaa Yao
- 5 National Cardiothoracic Centre, Korle Bu Teaching Hospital , Accra, Ghana
- 6 University of Ghana Medical School, University of Ghana , Accra, Ghana
| | - Emile Chimusa
- 1 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Jonathan Evans
- 1 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Emmanuel Okai
- 2 School of Medical Sciences, University of Cape Coast , Cape Coast, Ghana
- 7 Cape Coast Teaching Hospital , Cape Coast, Ghana
| | - Paul Kruszka
- 8 National Human Genome Research Institute, Medical Genetics Branch, National Institutes of Health , Bethesda, Maryland, USA
| | - Maximilian Muenke
- 8 National Human Genome Research Institute, Medical Genetics Branch, National Institutes of Health , Bethesda, Maryland, USA
| | - Gordon Awandare
- 9 Department of Biochemistry, WACCBIP, University of Ghana , Legon, Accra, Ghana
| | - Ambroise Wonkam
- 1 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Collet Dandara
- 1 Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
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13
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Liu S, Su Z, Tan S, Ni B, Pan H, Liu B, Wang J, Xiao J, Chen Q. Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease. Pediatr Cardiol 2017; 38:1226-1231. [PMID: 28687891 DOI: 10.1007/s00246-017-1649-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 06/02/2017] [Indexed: 12/22/2022]
Abstract
CITED2 gene is an important cardiac transcription factor that plays a fundamental role in the formation and development of embryonic cardiovascular. Previous studies have showed that knock-out of CITED2 in mice might result in various cardiac malformations. However, the mechanisms of CITED2 mutation on congenital heart disease (CHD) in Chinese Tibetan population are still poorly understood. In the present study, 187 unrelated Tibetan patients with CHD and 200 unrelated Tibetan healthy controls were screened for variants in the CITED2 gene; we subsequently identified one potential disease-causing mutation p.G143A in a 6-year-old girl with PDA and functional analyses of the mutation were carried out. Our study showed that the novel mutation of CITED2 significantly enhanced the expression activity of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia inducible factor 1-aipha (HIF-1A), which is closely related with embryonic cardiac development. As a result, CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease.
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Affiliation(s)
- Shiming Liu
- Qinghai High Altitude Medical Research Institute, No.7, Zhuanchang Road, West District, Xining, 810012, China
| | - Zhaobing Su
- Department of Cardiology, The Dongguan Affiliated Hospital of Medical College of Jinan University, The Fifth People's Hospital of Dongguan, 154 Humen Road, Humen, 523900, Guangdong, China
| | - Sainan Tan
- Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Changsha, China
| | - Bin Ni
- Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Changsha, China
| | - Hong Pan
- Center for Genetics, National Research Institute for Family Planning, Beijing, 100081, China
| | - Beihong Liu
- Center for Genetics, National Research Institute for Family Planning, Beijing, 100081, China
| | - Jing Wang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Jianmin Xiao
- Department of Cardiology, The Dongguan Affiliated Hospital of Medical College of Jinan University, The Fifth People's Hospital of Dongguan, 154 Humen Road, Humen, 523900, Guangdong, China.
| | - Qiuhong Chen
- Qinghai High Altitude Medical Research Institute, No.7, Zhuanchang Road, West District, Xining, 810012, China.
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14
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Pacheco-Leyva I, Matias AC, Oliveira DV, Santos JMA, Nascimento R, Guerreiro E, Michell AC, van De Vrugt AM, Machado-Oliveira G, Ferreira G, Domian I, Bragança J. CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells. Stem Cell Reports 2016; 7:1037-1049. [PMID: 27818139 PMCID: PMC5161512 DOI: 10.1016/j.stemcr.2016.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 10/05/2016] [Accepted: 10/06/2016] [Indexed: 01/07/2023] Open
Abstract
The transcriptional regulator CITED2 is essential for heart development. Here, we investigated the role of CITED2 in the specification of cardiac cell fate from mouse embryonic stem cells (ESC). The overexpression of CITED2 in undifferentiated ESC was sufficient to promote cardiac cell emergence upon differentiation. Conversely, the depletion of Cited2 at the onset of differentiation resulted in a decline of ESC ability to generate cardiac cells. Moreover, loss of Cited2 expression impairs the expression of early mesoderm markers and cardiogenic transcription factors (Isl1, Gata4, Tbx5). The cardiogenic defects in Cited2-depleted cells were rescued by treatment with recombinant CITED2 protein. We showed that Cited2 expression is enriched in cardiac progenitors either derived from ESC or mouse embryonic hearts. Finally, we demonstrated that CITED2 and ISL1 proteins interact physically and cooperate to promote ESC differentiation toward cardiomyocytes. Collectively, our results show that Cited2 plays a pivotal role in cardiac commitment of ESC.
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Affiliation(s)
- Ivette Pacheco-Leyva
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Ana Catarina Matias
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Daniel V Oliveira
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - João M A Santos
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Rita Nascimento
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Eduarda Guerreiro
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Anna C Michell
- Division of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Annebel M van De Vrugt
- Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3200, 185 Cambridge Street, Boston, MA 02114-2790, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA; Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Gisela Machado-Oliveira
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal
| | - Guilherme Ferreira
- DSM Biotechnology Center, Alexander Fleminglaan 1, 2613 AX Delft, the Netherlands
| | - Ibrahim Domian
- Cardiovascular Research Center, Massachusetts General Hospital, Charles River Plaza/CPZN 3200, 185 Cambridge Street, Boston, MA 02114-2790, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA
| | - José Bragança
- Regenerative Medicine Program, Department of Biomedical Sciences and Medicine, University of Algarve, 8005-139 Faro, Portugal; Centre for Biomedical Research - CBMR, University of Algarve, Campus of Gambelas, Building 8, Room 2.22, 8005-139 Faro, Portugal; ABC - Algarve Biomedical Centre, 8005-139 Faro, Portugal.
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15
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Abstract
Hypoxia inducible factors (HIFs) are α/β heterodimeric transcription factors that direct multiple cellular and systemic responses in response to changes in oxygen availability. The oxygen sensitive signal is generated by a series of iron and 2-oxoglutarate-dependent dioxygenases that catalyze post-translational hydroxylation of specific prolyl and asparaginyl residues in HIFα subunits and thereby promote their destruction and inactivation in the presence of oxygen. In hypoxia, these processes are suppressed allowing HIF to activate a massive transcriptional cascade. Elucidation of these pathways has opened several new fields of cardiovascular research. Here, we review the role of HIF hydroxylase pathways in cardiac development and in cardiovascular control. We also consider the current status, opportunities, and challenges of therapeutic modulation of HIF hydroxylases in the therapy of cardiovascular disease.
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Affiliation(s)
- Tammie Bishop
- From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Peter J Ratcliffe
- From the Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
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16
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Clark AL, Naya FJ. MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2. J Biol Chem 2015; 290:23162-72. [PMID: 26240138 DOI: 10.1074/jbc.m115.672659] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Indexed: 01/04/2023] Open
Abstract
Understanding cell cycle regulation in postmitotic cardiomyocytes may lead to new therapeutic approaches to regenerate damaged cardiac tissue. We have demonstrated previously that microRNAs encoded by the Gtl2-Dio3 noncoding RNA locus function downstream of the MEF2A transcription factor in skeletal muscle regeneration. We have also reported expression of these miRNAs in the heart. Here we investigated the role of two Gtl2-Dio3 miRNAs, miR-410 and miR-495, in cardiac muscle. Overexpression of miR-410 and miR-495 robustly stimulated cardiomyocyte DNA synthesis and proliferation. Interestingly, unlike our findings in skeletal muscle, these miRNAs did not modulate the activity of the WNT signaling pathway. Instead, these miRNAs targeted Cited2, a coactivator required for proper cardiac development. Consistent with miR-410 and miR-495 overexpression, siRNA knockdown of Cited2 in neonatal cardiomyocytes resulted in robust proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of VEGFA, a growth factor with proliferation-promoting effects. Therefore, miR-410 and miR-495 are among a growing number of miRNAs that have the ability to potently stimulate neonatal cardiomyocyte proliferation.
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Affiliation(s)
- Amanda L Clark
- From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215
| | - Francisco J Naya
- From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215
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17
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Kranc KR, Oliveira DV, Armesilla-Diaz A, Pacheco-Leyva I, Catarina Matias A, Luisa Escapa A, Subramani C, Wheadon H, Trindade M, Nichols J, Kaji K, Enver T, Bragança J. Acute Loss of Cited2 Impairs Nanog Expression and Decreases Self-Renewal of Mouse Embryonic Stem Cells. Stem Cells 2015; 33:699-712. [DOI: https:/doi.org/10.1002/stem.1889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Abstract
Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment of embryonic stem cells (ESC). While overexpression of the transcriptional regulator Cited2 sustains ESC pluripotency, its role in ESC functions remains unclear. Here, we show that Cited2 is important for proliferation, survival, and self-renewal of mouse ESC. We position Cited2 within the pluripotency gene regulatory network by defining Nanog, Tbx3, and Klf4 as its direct targets. We also demonstrate that the defects caused by Cited2 depletion are, at least in part, rescued by Nanog constitutive expression. Finally, we demonstrate that Cited2 is required for and enhances reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. Stem Cells 2015;33:699–712
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Affiliation(s)
- Kamil R. Kranc
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Daniel V. Oliveira
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
| | | | - Ivette Pacheco-Leyva
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
| | - Ana Catarina Matias
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
| | - Ana Luisa Escapa
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
| | - Chithra Subramani
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Helen Wheadon
- Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital, Glasgow, United Kingdom
| | - Marlene Trindade
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
| | - Jennifer Nichols
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom
| | - Keisuke Kaji
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Tariq Enver
- Stem Cell Laboratory UCL Cancer Institute, University College London, Paul O'Gorman Building, London, United Kingdom
| | - José Bragança
- Departamento de Ciências Biomédicas e Medicina Universidade do Algarve, Faro, Portugal
- IBB-Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de Gambelas, Faro, Portugal
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18
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Kranc KR, Oliveira DV, Armesilla-Diaz A, Pacheco-Leyva I, Catarina Matias A, Luisa Escapa A, Subramani C, Wheadon H, Trindade M, Nichols J, Kaji K, Enver T, Bragança J. Acute loss of Cited2 impairs Nanog expression and decreases self-renewal of mouse embryonic stem cells. Stem Cells 2015; 33:699-712. [PMID: 25377420 PMCID: PMC4583779 DOI: 10.1002/stem.1889] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/16/2014] [Accepted: 10/11/2014] [Indexed: 12/23/2022]
Abstract
Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well as delineating the interactions within the complex network is key to understanding self-renewal and early cell fate commitment of embryonic stem cells (ESC). While overexpression of the transcriptional regulator Cited2 sustains ESC pluripotency, its role in ESC functions remains unclear. Here, we show that Cited2 is important for proliferation, survival, and self-renewal of mouse ESC. We position Cited2 within the pluripotency gene regulatory network by defining Nanog, Tbx3, and Klf4 as its direct targets. We also demonstrate that the defects caused by Cited2 depletion are, at least in part, rescued by Nanog constitutive expression. Finally, we demonstrate that Cited2 is required for and enhances reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells.
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Affiliation(s)
- Kamil R Kranc
- MRC Centre for Regenerative Medicine, University of EdinburghEdinburgh, United Kingdom
| | - Daniel V Oliveira
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
| | | | - Ivette Pacheco-Leyva
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
| | - Ana Catarina Matias
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
| | - Ana Luisa Escapa
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
| | - Chithra Subramani
- MRC Centre for Regenerative Medicine, University of EdinburghEdinburgh, United Kingdom
| | - Helen Wheadon
- Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General HospitalGlasgow, United Kingdom
| | - Marlene Trindade
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
| | - Jennifer Nichols
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of CambridgeTennis Court Road, Cambridge, United Kingdom
| | - Keisuke Kaji
- MRC Centre for Regenerative Medicine, University of EdinburghEdinburgh, United Kingdom
| | - Tariq Enver
- Stem Cell Laboratory, UCL Cancer Institute, University College LondonPaul O'Gorman Building, London, United Kingdom
| | - José Bragança
- Departamento de Ciências Biomédicas e Medicina, Universidade do AlgarveFaro, Portugal
- IBB-Centro de Biomedicina Molecular e Estrutural, Universidade do Algarve, Campus de GambelasFaro, Portugal
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19
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Cited2 is required in trophoblasts for correct placental capillary patterning. Dev Biol 2014; 392:62-79. [DOI: 10.1016/j.ydbio.2014.04.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 04/21/2014] [Accepted: 04/23/2014] [Indexed: 01/14/2023]
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20
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Liu Y, Wang F, Wu Y, Tan S, Wen Q, Wang J, Zhu X, Wang X, Li C, Ma X, Pan H. Variations of CITED2 are associated with congenital heart disease (CHD) in Chinese population. PLoS One 2014; 9:e98157. [PMID: 24848765 PMCID: PMC4029912 DOI: 10.1371/journal.pone.0098157] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 04/29/2014] [Indexed: 01/27/2023] Open
Abstract
CITED2 was identified as a cardiac transcription factor which is essential to the heart development. Cited2-deficient mice showed cardiac malformations, adrenal agenesis and neural crest defects. To explore the potential impact of mutations in CITED2 on congenital heart disease (CHD) in humans, we screened the coding region of CITED2 in a total of 700 Chinese people with congenital heart disease and 250 healthy individuals as controls. We found five potential disease-causing mutations, p.P140S, p.S183L, p.S196G, p.Ser161delAGC and p. Ser192_Gly193delAGCGGC. Two mammalian two-hybrid assays showed that the last four mutations significantly affected the interaction between p300CH1 and CITED2 or HIF1A. Further studies showed that four CITED2 mutations recovered the promoter activity of VEGF by decreasing its competitiveness with HIF1A for binding to p300CH1 and three mutations decreased the consociation of TFAP2C and CITED2 in the transactivation of PITX2C. Both VEGF and PITX2C play very important roles in cardiac development. In conclusion, we demonstrated that CITED2 has a potential causative impact on congenital heart disease.
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Affiliation(s)
- Yan Liu
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
| | - Fengyu Wang
- Henan Research Institute of Population and Family Planning, Key Laboratory of Population Defects Intervention Technology of Henan Province, Zhengzhou, China
| | - Yuan Wu
- Cardiac Surgery Department, Xiamen Heart Center, Organ Transplantation Institute of Xiamen University, Xiang'an District, Xiamen, China
| | - Sainan Tan
- Key Laboratory of Genetics and Birth Health of Hunan Province, Family Planning Institute of Hunan Province, Chang sha, China
| | - Qiaolian Wen
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
| | - Jing Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaomei Zhu
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
| | - Xi Wang
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
| | - Congmin Li
- Henan Research Institute of Population and Family Planning, Key Laboratory of Population Defects Intervention Technology of Henan Province, Zhengzhou, China
- * E-mail: (CL); (HP); (XM)
| | - Xu Ma
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
- World Health Organization Collaborating Centre for Research in Human Reproduction, Beijing, China
- * E-mail: (CL); (HP); (XM)
| | - Hong Pan
- Graduate School, Peking Union Medical College, Beijing, China
- National Research Institute for Family Planning, Beijing, China
- * E-mail: (CL); (HP); (XM)
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Xu M, Wu X, Li Y, Yang X, Hu J, Zheng M, Tian J. CITED2 mutation and methylation in children with congenital heart disease. J Biomed Sci 2014; 21:7. [PMID: 24456003 PMCID: PMC3917535 DOI: 10.1186/1423-0127-21-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 01/20/2014] [Indexed: 12/29/2022] Open
Abstract
Background The occurrence of Congenital Heart Disease (CHD) is resulted from either genetic or environmental factors or the both. The CITED2 gene deletion or mutation is associated with the development of cardiac malformations. In this study, we have investigated the role of CITED2 gene mutation and methylation in the development of Congenital Heart Disease in pediatric patients in China. Results We have screened 120 pediatric patients with congenital heart disease. Among these patients, 4 cases were detected to carry various CITED2 gene heterozygous mutations (c.550G > A, c.574A > G, c.573-578del6) leading correspondingly to the alterations of amino acid sequences in Gly184Ser, Ser192Gly, and Ser192fs, respectively. No CITED2 gene mutations were detected in the control group. At the same time, we found that CITED2 mutations could inhibit TFAP2c expression. In addition, we have demonstrated that abnormal CITED2 gene methylation was detected in most of the tested pediatric patients with CHD, which leads to a decrease of CITED2 transcription activities. Conclusions Our study suggests that CITED2 gene mutations and methylation may play an important role in the development of pediatric congenital heart disease.
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Affiliation(s)
| | - Xiaoyun Wu
- Department of Cardiology, Children's Hospital of Chongqing Medical University, 136 Zhongshan Er Road, Chongqing 400014, P,R, China.
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Devakanmalai GS, Zumrut HE, Ozbudak EM. Cited3 activates Mef2c to control muscle cell differentiation and survival. Biol Open 2013; 2:505-14. [PMID: 23789100 PMCID: PMC3654270 DOI: 10.1242/bio.20132550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 03/25/2013] [Indexed: 01/13/2023] Open
Abstract
Vertebrate muscle development occurs through sequential differentiation of cells residing in somitic mesoderm – a process that is largely governed by transcriptional regulators. Our recent spatiotemporal microarray study in zebrafish has identified functionally uncharacterized transcriptional regulators that are expressed at the initial stages of myogenesis. cited3 is one such novel gene encoding a transcriptional coactivator, which is expressed in the precursors of oxidative slow-twitch myofibers. Our experiments placed cited3 into a gene regulatory network, where it acts downstream of Hedgehog signaling and myoD/myf5 but upstream of mef2c. Knockdown of expression of cited3 by antisense morpholino oligonucleotides impaired muscle cell differentiation and growth, caused muscle cell death and eventually led to total immotility. Transplantation experiments demonstrated that Cited3 cell-autonomously activates the expression of mef2c in slow myofibers, while it non-cell-autonomously regulates expression of structural genes in fast myofibers. Restoring expression of cited3 or mef2c rescued all the cited3 loss-of-function phenotypes. Protein truncation experiments revealed the functional necessity of C-terminally conserved domain of Cited3, which is known to mediate interactions of Cited-family proteins with histone acetylases. Our findings demonstrate that Cited3 is a critical transcriptional coactivator functioning during muscle differentiation and its absence leads to defects in terminal differentiation and survival of muscle cells.
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Li Q, Ramírez-Bergeron DL, Dunwoodie SL, Yang YC. Cited2 gene controls pluripotency and cardiomyocyte differentiation of murine embryonic stem cells through Oct4 gene. J Biol Chem 2012; 287:29088-100. [PMID: 22761414 DOI: 10.1074/jbc.m112.378034] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cited2 (CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail 2) is a transcriptional modulator critical for the development of multiple organs. Although many Cited2-mediated phenotypes and molecular events have been well characterized using in vivo genetic murine models, Cited2-directed cell fate decision in embryonic stem cells (ESCs) remains elusive. In this study, we examined the role of Cited2 in the maintenance of stemness and pluripotency of murine ESCs by a gene-targeting approach. Cited2 knock-out (Cited2(Δ/-), KO) ESCs display defective differentiation. Loss of Cited2 in differentiating ESCs results in delayed silencing of the genes involved in the maintenance of pluripotency and self-renewal of stem cells (Oct4, Klf4, Sox2, and c-Myc) and the disturbance in cardiomyocyte, hematopoietic, and neuronal differentiation. In addition, Cited2 KO ESCs experience a delayed induction of cardiomyocyte differentiation-associated proteins, NFAT3 (along with the reduced expression of NFAT3 target genes, Nkx2.5 and β-MHC), N-cadherin, and smooth muscle actin. CITED2 is recruited to the Oct4 promoter to regulate its expression during early ESC differentiation. This is the first demonstration that Cited2 controls ESC pluripotency and differentiation via direct regulation of Oct4 gene expression.
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Affiliation(s)
- Qiang Li
- Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
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