title: Secretion of Down Syndrome Critical Region 1 Isoform 4 in Ischemic Retinal Ganglion Cells Displays Anti-Angiogenic Properties Via NFATc1-Dependent Pathway.
abstract: Down syndrome candidate region 1 (DSCR1) has two differentially regulated isoforms (DSCR1-1 and DSCR1-4) and is reported to play a role in a number of physiological processes, such as the inhibition of cardiac hypertrophy, attenuation of angiogenesis and carcinogenesis, and protection against neuronal death. However, the function of DSCR1 in the retina is still not clear. Therefore, we analyzed the expression and location of DSCR1 in the retina of neonatal mice with oxygen-induced retinopathy (OIR), and studied its effects on angiogenesis. The neonatal C57BL/6J mice were exposed to 75 % O2for 5 days from postnatal day 7 (P7) to P12. At P12, the mice were returned to 21 % O2at room air. The primary retinal ganglion cells (RGCs) were exposed to hypoxia (93 % N2, 5 % CO2, and 2 % O2) at 37 °C for 36 h. And then the mouse retinal microvascular endothelial cells (mRMECs) were treated with 25 ng/mL vascular endothelial growth factor (VEGF) or culture medium conditioned by hypoxic RGCs alone, hypoxic RGCs treated with DSCR1-4-siRNA (siDSCR1-4) or hypoxic RGCs treated with siDSCR1-4 and 200 ng/mL cyclosporin A (CsA), and then primed with VEGF (25 ng/mL). The expression of DSCR1-4 increased strongly at P16 after OIR. There was no change in messenger RNA (mRNA) expression of DSCR1-1 at P16 after OIR. The increased DSCR1 was mainly located in the RGCs of avascular retina. In addition, DSCR1-4 expression was increased in primary RGCs after hypoxia exposure. There was no change in mRNA expression of DSCR1-1 in primary RGCs after hypoxia exposure. Moreover, DSCR1-4 produced by hypoxic RGCs showed anti-angiogenic properties, with decreased cell proliferation, migration, tube formation, and inflammatory cytokines production. These properties were due to inhibited nuclear factor of activated T cell (NFATc) 1 dephosphorylation and translocation into nuclear in VEGF-treated mRMECs. Using siRNA-mediated knockdown of DSCR1-4 and NFATc1 inhibitor (Cs A) further demonstrated the inhibitory effect of DSCR1-4 on angiogenic properties in VEGF-induced mRMECs, and this effect was NFATc1-dependent. This report describes a novel effect of DSCR1-4 in the aspect of anti-angiogenesis, suggesting potential therapeutic strategies for proliferative retinopathies.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Boyu
authors.initials: B
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Vision Sciences and Key Laboratory of Myopia of State Health Ministry, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qinmeng
authors.initials: Q
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Qiaochu
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China. hjjing@mail.sysu.edu.cn.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510000, Guangdong Province, People's Republic of China. liangxlsums@qq.com.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; C108612:RCAN1 protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; DSCR1; NFATc1; Proliferative retinopathies; Retinal ganglion cells