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Identification and functional characterization of hypoxia-induced endoplasmic reticulum stress regulating lncRNA (HypERlnc) in pericytes

Item Type:Article
Title:Identification and functional characterization of hypoxia-induced endoplasmic reticulum stress regulating lncRNA (HypERlnc) in pericytes
Creators Name:Bischoff, F.C. and Werner, A. and John, D. and Boeckel, J.-N. and Melissari, M.-T. and Grote, P. and Glaser, S.F. and Demolli, S. and Uchida, S. and Michalik, K.M. and Meder, B. and Katus, H.A. and Haas, J. and Chen, W. and Pullamsetti, S.S. and Seeger, W. and Zeiher, A.M. and Dimmeler, S. and Zehendner, C.M.
Abstract:RATIONALE: Pericytes are essential for vessel maturation and endothelial barrier function. Long noncoding RNAs regulate many cellular functions, but their role in pericyte biology remains unexplored. OBJECTIVE: Here, we investigate the effect of hypoxia-induced endoplasmic reticulum stress regulating long noncoding RNAs (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: RNA sequencing in human primary pericytes identified hypoxia-regulated long noncoding RNAs, including HypERlnc. Silencing of HypERlnc decreased cell viability and proliferation and resulted in pericyte dedifferentiation, which went along with increased endothelial permeability in cocultures consisting of human primary pericyte and human coronary microvascular endothelial cells. Consistently, Cas9-based transcriptional activation of HypERlnc was associated with increased expression of pericyte marker genes. Moreover, HypERlnc knockdown reduced endothelial-pericyte recruitment in Matrigel assays (P<0.05). Mechanistically, transcription factor reporter arrays demonstrated that endoplasmic reticulum stress-related transcription factors were prominently activated by HypERlnc knockdown, which was confirmed via immunoblotting for the endoplasmic reticulum stress markers IRE1α (P<0.001), ATF6 (P<0.01), and soluble BiP (P<0.001). Kyoto encyclopedia of genes and gene ontology pathway analyses of RNA sequencing experiments after HypERlnc knockdown indicate a role in cardiovascular disease states. Indeed, HypERlnc expression was significantly reduced in human cardiac tissue from patients with heart failure (P<0.05; n=19) compared with controls. In addition, HypERlnc expression significantly correlated with pericyte markers in human lungs derived from patients diagnosed with idiopathic pulmonary arterial hypertension and from donor lungs (n=14). CONCLUSIONS: Here, we show that HypERlnc regulates human pericyte function and the endoplasmic reticulum stress response. In addition, RNA sequencing analyses in conjunction with reduced expression of HypERlnc in heart failure and correlation with pericyte markers in idiopathic pulmonary arterial hypertension indicate a role of HypERlnc in human cardiopulmonary disease.
Keywords:Cardiovascular Diseases, Heart Diseases, Long Noncoding RNA, Pericytes, Pulmonary Heart Disease, Animals, Mice
Source:Circulation Research
Publisher:American Heart Association
Page Range:368-375
Date:4 August 2017
Official Publication:https://doi.org/10.1161/CIRCRESAHA.116.310531
PubMed:View item in PubMed

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