Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.

Autor:	Winter H; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany., Winski G; Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden., Busch A; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; Division of Vascular and Endovascular Surgery, Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, Carl Gustav Carus and University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany., Chernogubova E; Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Fasolo F; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany., Wu Z; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany., Bäcklund A; Department of Medicine, Karolinska Institutet, Stockholm, Sweden., Khomtchouk BB; Department of BioHealth Informatics, Indiana University, Indianapolis, IN, USA; Krannert Cardiovascular Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology & Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA., Van Booven DJ; John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA., Sachs N; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany., Eckstein HH; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany., Wittig I; Functional Proteomics, Institute of Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, Germany; German Center for Cardiovascular Research DZHK, Partner Site Frankfurt Rhine-Main, 60590 Frankfurt am Main, Germany., Boon RA; German Center for Cardiovascular Research DZHK, Partner Site Frankfurt Rhine-Main, 60590 Frankfurt am Main, Germany; Institute of Cardiovascular Regeneration, Goethe University, 60590 Frankfurt am Main, Germany; Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, 1081 Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Microcirculation, 1105 Amsterdam, the Netherlands., Jin H; Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden., Maegdefessel L; Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Berlin, Germany; Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: lars.maegdefessel@tum.de.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Jun 07; Vol. 31 (6), pp. 1775-1790. Date of Electronic Publication: 2023 May 05.
DOI:	10.1016/j.ymthe.2023.04.020
Abstrakt:	Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases. Competing Interests: Declaration of interests L.M. is a scientific consultant and adviser for Novo Nordisk (Malov, Denmark), DrugFarm (Shanghai, China), and Angiolutions (Hannover, Germany), and received research funds from Roche Diagnostics (Rotkreuz, Switzerland) and Novo Nordisk (Malov, Denmark). (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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