LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy

Long non‐coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial‐associated lncRNA ( VEAL2 ) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish ( veal2 gib005Δ8/+ ) induced crani...

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Veröffentlicht in:	The EMBO journal 2021-08, Vol.40 (15), p.e107134-n/a
Hauptverfasser:	Sehgal, Paras, Mathew, Samatha, Sivadas, Ambily, Ray, Arjun, Tanwar, Jyoti, Vishwakarma, Sushma, Ranjan, Gyan, Shamsudheen, K V, Bhoyar, Rahul C, Pateria, Abhishek, Leonard, Elvin, Lalwani, Mukesh, Vats, Archana, Pappuru, Rajeev R, Tyagi, Mudit, Jakati, Saumya, Sengupta, Shantanu, B K, Binukumar, Chakrabarti, Subhabrata, Kaur, Inderjeet, Motiani, Rajender K, Scaria, Vinod, Sivasubbu, Sridhar
Format:	Artikel
Sprache:	eng
Schlagworte:	Baits Competition Danio rerio Diabetes Diabetes mellitus Diabetic retinopathy diacylglycerol Diglycerides Ectopic expression EMBO05 EMBO36 EMBO46 Endothelial cells endothelial permeability Endothelium Hemorrhage In vivo methods and tests Kinases long non‐coding RNA Non-coding RNA Permeability Protein kinase C protein kinase C beta Proteins Retinopathy Zebrafish
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creator	Sehgal, Paras Mathew, Samatha Sivadas, Ambily Ray, Arjun Tanwar, Jyoti Vishwakarma, Sushma Ranjan, Gyan Shamsudheen, K V Bhoyar, Rahul C Pateria, Abhishek Leonard, Elvin Lalwani, Mukesh Vats, Archana Pappuru, Rajeev R Tyagi, Mudit Jakati, Saumya Sengupta, Shantanu B K, Binukumar Chakrabarti, Subhabrata Kaur, Inderjeet Motiani, Rajender K Scaria, Vinod Sivasubbu, Sridhar
description	Long non‐coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial‐associated lncRNA ( VEAL2 ) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish ( veal2 gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2 . Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability. Synopsis Protein kinase C beta (PRKCB) promotes vascular permeability, and its hyper‐activation has been linked to diabetic retinopathy. Here, the novel, evolutionarily conserved lncRNA VEAL2 is shown to inhibit PRKCB activity and junctional permeability in zebrafish and in human vascular endothelium. VEAL2 inhibits vascular permeability and modulates junctional assembly in zebrafish vasculature and in human endothelial cells. VEAL2 inhibits PRKCB activity by competing with diacylglycerol binding to its C1 domain. The levels of VEAL2 are reduced in retinal choroid tissue of patients with diabetic retinopathy. Ectopic expression of VEAL2 ameliorates the hyperglycemic disease pathophysiology in human endothelial cells. Graphical Abstract The evolutionarily conserved lncRNA VEAL2 enhances junctional integrity in developing zebrafish vasculature and in hyperglycemic vascular endothelium in humans.
doi_str_mv	10.15252/embj.2020107134
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Here, we investigated the role of a novel vascular endothelial‐associated lncRNA ( VEAL2 ) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish ( veal2 gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2 . Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability. Synopsis Protein kinase C beta (PRKCB) promotes vascular permeability, and its hyper‐activation has been linked to diabetic retinopathy. Here, the novel, evolutionarily conserved lncRNA VEAL2 is shown to inhibit PRKCB activity and junctional permeability in zebrafish and in human vascular endothelium. VEAL2 inhibits vascular permeability and modulates junctional assembly in zebrafish vasculature and in human endothelial cells. VEAL2 inhibits PRKCB activity by competing with diacylglycerol binding to its C1 domain. The levels of VEAL2 are reduced in retinal choroid tissue of patients with diabetic retinopathy. Ectopic expression of VEAL2 ameliorates the hyperglycemic disease pathophysiology in human endothelial cells. Graphical Abstract The evolutionarily conserved lncRNA VEAL2 enhances junctional integrity in developing zebrafish vasculature and in hyperglycemic vascular endothelium in humans.</description><identifier>ISSN: 0261-4189</identifier><identifier>EISSN: 1460-2075</identifier><identifier>DOI: 10.15252/embj.2020107134</identifier><identifier>PMID: 34180064</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Baits ; Competition ; Danio rerio ; Diabetes ; Diabetes mellitus ; Diabetic retinopathy ; diacylglycerol ; Diglycerides ; Ectopic expression ; EMBO05 ; EMBO36 ; EMBO46 ; Endothelial cells ; endothelial permeability ; Endothelium ; Hemorrhage ; In vivo methods and tests ; Kinases ; long non‐coding RNA ; Non-coding RNA ; Permeability ; Protein kinase C ; protein kinase C beta ; Proteins ; Retinopathy ; Zebrafish</subject><ispartof>The EMBO journal, 2021-08, Vol.40 (15), p.e107134-n/a</ispartof><rights>The Author(s) 2021</rights><rights>2021 The Authors. 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Here, we investigated the role of a novel vascular endothelial‐associated lncRNA ( VEAL2 ) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish ( veal2 gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2 . Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability. Synopsis Protein kinase C beta (PRKCB) promotes vascular permeability, and its hyper‐activation has been linked to diabetic retinopathy. Here, the novel, evolutionarily conserved lncRNA VEAL2 is shown to inhibit PRKCB activity and junctional permeability in zebrafish and in human vascular endothelium. VEAL2 inhibits vascular permeability and modulates junctional assembly in zebrafish vasculature and in human endothelial cells. VEAL2 inhibits PRKCB activity by competing with diacylglycerol binding to its C1 domain. The levels of VEAL2 are reduced in retinal choroid tissue of patients with diabetic retinopathy. Ectopic expression of VEAL2 ameliorates the hyperglycemic disease pathophysiology in human endothelial cells. Graphical Abstract The evolutionarily conserved lncRNA VEAL2 enhances junctional integrity in developing zebrafish vasculature and in hyperglycemic vascular endothelium in humans.</description><subject>Baits</subject><subject>Competition</subject><subject>Danio rerio</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic retinopathy</subject><subject>diacylglycerol</subject><subject>Diglycerides</subject><subject>Ectopic expression</subject><subject>EMBO05</subject><subject>EMBO36</subject><subject>EMBO46</subject><subject>Endothelial cells</subject><subject>endothelial permeability</subject><subject>Endothelium</subject><subject>Hemorrhage</subject><subject>In vivo methods and tests</subject><subject>Kinases</subject><subject>long non‐coding RNA</subject><subject>Non-coding RNA</subject><subject>Permeability</subject><subject>Protein kinase C</subject><subject>protein kinase C 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Paras ; Mathew, Samatha ; Sivadas, Ambily ; Ray, Arjun ; Tanwar, Jyoti ; Vishwakarma, Sushma ; Ranjan, Gyan ; Shamsudheen, K V ; Bhoyar, Rahul C ; Pateria, Abhishek ; Leonard, Elvin ; Lalwani, Mukesh ; Vats, Archana ; Pappuru, Rajeev R ; Tyagi, Mudit ; Jakati, Saumya ; Sengupta, Shantanu ; B K, Binukumar ; Chakrabarti, Subhabrata ; Kaur, Inderjeet ; Motiani, Rajender K ; Scaria, Vinod ; Sivasubbu, Sridhar</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4964-acda15264bacc0162170de5ef6b67dff549107faa08e6b6df0e1e0aa824b98fa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Baits</topic><topic>Competition</topic><topic>Danio rerio</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetic retinopathy</topic><topic>diacylglycerol</topic><topic>Diglycerides</topic><topic>Ectopic 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J</stitle><date>2021-08-02</date><risdate>2021</risdate><volume>40</volume><issue>15</issue><spage>e107134</spage><epage>n/a</epage><pages>e107134-n/a</pages><issn>0261-4189</issn><eissn>1460-2075</eissn><abstract>Long non‐coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial‐associated lncRNA ( VEAL2 ) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish ( veal2 gib005Δ8/+ ) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2 . Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability. Synopsis Protein kinase C beta (PRKCB) promotes vascular permeability, and its hyper‐activation has been linked to diabetic retinopathy. Here, the novel, evolutionarily conserved lncRNA VEAL2 is shown to inhibit PRKCB activity and junctional permeability in zebrafish and in human vascular endothelium. VEAL2 inhibits vascular permeability and modulates junctional assembly in zebrafish vasculature and in human endothelial cells. VEAL2 inhibits PRKCB activity by competing with diacylglycerol binding to its C1 domain. The levels of VEAL2 are reduced in retinal choroid tissue of patients with diabetic retinopathy. Ectopic expression of VEAL2 ameliorates the hyperglycemic disease pathophysiology in human endothelial cells. 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ispartof	The EMBO journal, 2021-08, Vol.40 (15), p.e107134-n/a
issn	0261-4189 1460-2075
language	eng
recordid	cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8327952
source	Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature OA Free Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); PubMed Central; Free Full-Text Journals in Chemistry
subjects	Baits Competition Danio rerio Diabetes Diabetes mellitus Diabetic retinopathy diacylglycerol Diglycerides Ectopic expression EMBO05 EMBO36 EMBO46 Endothelial cells endothelial permeability Endothelium Hemorrhage In vivo methods and tests Kinases long non‐coding RNA Non-coding RNA Permeability Protein kinase C protein kinase C beta Proteins Retinopathy Zebrafish
title	LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy
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