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The Vascular LncRNA VELRP Defines an Epigenetic Checkpoint in Hyperproliferation of Pulmonary Arterial Smooth Muscle Cell
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A4621 - The Vascular LncRNA VELRP Defines an Epigenetic Checkpoint in Hyperproliferation of Pulmonary Arterial Smooth Muscle Cell
Author Block: J. Chen1, J. Guo1, J. Chen2, D. Gou1; 1College of Life Sciences, Shenzhen University, Shenzhen, China, 2Dept of Medicine, Univ of Illinois at Chicago, Chicago, IL, United States.
RATIONALE: Vascular remodeling mediated by hyperproliferation of pulmonary arterial smooth muscle cell (PASMC) is implicated in development of pulmonary artery hypertension (PAH). Misregulation of platelet-derived growth factor BB (PDGF-BB) activity can lead to disordered vascular remodeling through modulating PASMC proliferation, however, little is known about the role of long noncoding RNA (lncRNA) during this process.
METHODS: Quantitative real-time PCR was performed to investigate the expression of lncRNA in different tissues of rat or in pulmonary artery of monocrotaline (MCT)-induced PAH rat. Lenti-virus was used to inhibit or over-express the lncRNA. The expression change of transcriptome induced by lncRNA knockdown was assessed through RNA sequencing (RNA-seq). Proliferation of PASMC was investigated via EdU incorporation assay, MTS assay and PCNA detection. RNA of nucleus and cytoplasm was separated to explore the localization of lncRNA. The promoter activity of lncRNA was detected through a dual luciferase (firefly/renilla) system. Activity of related kinase was repressed using corresponding inhibitor.
RESULTS: Previously, we have identified a group of differentially expressed lncRNAs in response to PDGF-BB treatment in rat PASMC. In this work, one of the up-regulated lncRNAs was found to be expressed mainly in vessels, hence named Vessel Enriched Long non-coding RNA regulated by PDGF-BB (VELRP). Moreover, expression of VELRP was increased significantly in the pulmonary artery of MCT-induced PAH rat and the PASMC isolated from patients with inherited PAH. A series of gene clusters were founded to be expressed differentially when VELRP was knocked down in rat PASMC. Interestingly, these genes were significantly enriched in regulating the growth of cell. Coincidently, knockdown of VELRP reduced the proliferation of rat or human PASMC while overexpression of VELRP promoted proliferation of rat or human PASMC in the other hand. Mechanistically, VELRP was found to locate mainly in the nucleus and repress the methylation of the fourth lysine in histone 3 (H3K4), reducing the expression of cyclin-dependent kinases (CDK1, 2, 4, 5). In addition, expression of VELRP in rat and human PASMC was upregulated by PDGF-BB through JNK/p53 signaling.
CONCLUSIONS: Our data identified a conservative vascular lncRNA, VELRP, which was upregulated by PDGF-BB through JNK/p53 signaling. VELRP functioned as a regulator of PASMC proliferation via promoting H3K4 methylation, and was implicated in the development of PAH.
Author Block: J. Chen1, J. Guo1, J. Chen2, D. Gou1; 1College of Life Sciences, Shenzhen University, Shenzhen, China, 2Dept of Medicine, Univ of Illinois at Chicago, Chicago, IL, United States.
RATIONALE: Vascular remodeling mediated by hyperproliferation of pulmonary arterial smooth muscle cell (PASMC) is implicated in development of pulmonary artery hypertension (PAH). Misregulation of platelet-derived growth factor BB (PDGF-BB) activity can lead to disordered vascular remodeling through modulating PASMC proliferation, however, little is known about the role of long noncoding RNA (lncRNA) during this process.
METHODS: Quantitative real-time PCR was performed to investigate the expression of lncRNA in different tissues of rat or in pulmonary artery of monocrotaline (MCT)-induced PAH rat. Lenti-virus was used to inhibit or over-express the lncRNA. The expression change of transcriptome induced by lncRNA knockdown was assessed through RNA sequencing (RNA-seq). Proliferation of PASMC was investigated via EdU incorporation assay, MTS assay and PCNA detection. RNA of nucleus and cytoplasm was separated to explore the localization of lncRNA. The promoter activity of lncRNA was detected through a dual luciferase (firefly/renilla) system. Activity of related kinase was repressed using corresponding inhibitor.
RESULTS: Previously, we have identified a group of differentially expressed lncRNAs in response to PDGF-BB treatment in rat PASMC. In this work, one of the up-regulated lncRNAs was found to be expressed mainly in vessels, hence named Vessel Enriched Long non-coding RNA regulated by PDGF-BB (VELRP). Moreover, expression of VELRP was increased significantly in the pulmonary artery of MCT-induced PAH rat and the PASMC isolated from patients with inherited PAH. A series of gene clusters were founded to be expressed differentially when VELRP was knocked down in rat PASMC. Interestingly, these genes were significantly enriched in regulating the growth of cell. Coincidently, knockdown of VELRP reduced the proliferation of rat or human PASMC while overexpression of VELRP promoted proliferation of rat or human PASMC in the other hand. Mechanistically, VELRP was found to locate mainly in the nucleus and repress the methylation of the fourth lysine in histone 3 (H3K4), reducing the expression of cyclin-dependent kinases (CDK1, 2, 4, 5). In addition, expression of VELRP in rat and human PASMC was upregulated by PDGF-BB through JNK/p53 signaling.
CONCLUSIONS: Our data identified a conservative vascular lncRNA, VELRP, which was upregulated by PDGF-BB through JNK/p53 signaling. VELRP functioned as a regulator of PASMC proliferation via promoting H3K4 methylation, and was implicated in the development of PAH.
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