A Novel Angiotensin II Induced Long Non‐coding RNA GIVER Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells
| Autor: | Wei Wang, Mei Wang, Marpadga A. Reddy, Kenneth Stapleton, Zhuo Chen, Xinyue Zhang, Parijat Senapati, Qinghao Zhao, Linda Lanting, Bin Zhang, Mitsuo Kato, Haitong Zhang, Yongjian Wu, Qianyun Guo, Hyung Jung Oh, Vishnu Amaram, Rama Natarajan, Sadhan Das, Amy Leung, Erli Zhang |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Vascular smooth muscle Physiology Myocytes Smooth Muscle Cell Inflammation medicine.disease_cause Biochemistry Article Muscle Smooth Vascular Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Smooth muscle Genetics medicine Animals Humans Molecular Biology Cells Cultured Cell Proliferation chemistry.chemical_classification Reactive oxygen species Chemistry Angiotensin II Long non-coding RNA Rats Cell biology Mice Inbred C57BL Oxidative Stress medicine.anatomical_structure 030104 developmental biology 030220 oncology & carcinogenesis Hypertension cardiovascular system NADPH Oxidase 1 Cytokines RNA Long Noncoding medicine.symptom Cardiology and Cardiovascular Medicine human activities Oxidative stress Biotechnology |
| Zdroj: | The FASEB Journal. 32 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fasebj.2018.32.1_supplement.525.6 |
| Popis: | Rationale: AngII (angiotensin II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long noncoding RNAs have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear. Objective: To investigate the regulation and functions of a novel long noncoding RNA growth factor– and proinflammatory cytokine–induced vascular cell-expressed RNA ( Giver ), in AngII-mediated VSMC dysfunction. Methods and Results: RNA-sequencing and real-time quantitative polymerase chain reactions revealed that treatment of rat VSMC with AngII increased the expression of Giver and Nr4a3 , an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH (fluorescence in situ hybridization) and subcellular fractionation showed predominantly nuclear localization of Giver . AngII increased Giver expression via recruitment of Nr4a3 to Giver promoter. Microarray profiling and real-time quantitative polymerase chain reaction validation in VSMC showed that Giver knockdown attenuated the expression of genes involved in oxidative stress ( Nox1 ) and inflammation ( Il6 , Ccl2 , Tnf ) but increased Nr4a3 . Conversely, endogenous Giver overexpression showed opposite effects supporting its role in oxidative stress and inflammation. Chromatin immunoprecipitation assays showed Giver overexpression also increased Pol II (RNA polymerase II) enrichment and decreased repressive histone modification histone H3 trimethylation on lysine 27 at Nox1 and inflammatory gene promoters. Accordingly, Giver knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA-pulldown combined with mass spectrometry showed Giver interacts with nuclear and chromatin remodeling proteins and corepressors, including NONO (non-pou domain-containing octamer-binding protein). Moreover, NONO knockdown elicited similar effects as Giver knockdown on the expression of key Giver -regulated genes. Notably, GIVER and NR4A3 were increased in AngII-treated human VSMC and in arteries from hypertensive patients but attenuated in hypertensive patients treated with ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers. Furthermore, human GIVER also exhibits partial functional conservation with rat Giver . Conclusions: Giver and its regulator Nr4a3 are important players in AngII-mediated VSMC dysfunction and could be novel targets for antihypertensive therapy. |
| Databáze: | OpenAIRE |
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