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Published on: April 24, 2021
Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA
Florian C Bischoff1, Astrid Werner1, David John1
1From the Institute of Cardiovascular Regeneration, Centre of Molecular Medicine (F.C.B., A.W., D.J., M.-T.M., P.G., S.F.G., S.D., S.U., K.M.M., S.D., C.M.Z.); ZIM III, Department of Cardiology (F.C.B., A.W., S.F.G., A.M.Z., C.M.Z.), Goethe University, Frankfurt am Main, Germany; Department of Internal Medicine III, University of Heidelberg, Germany (J.-N.B., B.M., H.A.K., J.H.); DZHK (Deutsches Zentrum für Herz-Kreislaufforschung), Berlin, Germany (F.C.B., D.J., J.-N.B., S.D., S.U., B.M., H.A.K., J.H., W.C., A.M.Z., S.D., C.M.Z.); Cardiovascular Innovation Institute, University of Louisville, KY (S.U.); Laboratory for Novel Sequencing Technology, Functional and Medical Genomics, Berlin Institute for Medical Systems Biology, Max-Delbrück-Centrum für Molekulare Medizin, Germany (W.C.); Department of Biology, Southern University of Science and Technology, Shenzhen, China (W.C.); Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany (S.S.P., W.S.); Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the DZL, Justus Liebig University, Germany (S.S.P., W.S.).
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.
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