@article{2b8d8404283048ce980e3fa4c55a763b,
title = "Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression",
abstract = "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.",
keywords = "aortic aneurysm, atherosclerosis, long non-coding RNAs, proliferation, smooth muscle cell, therapeutics, vascular disease",
author = "Hanna Winter and Greg Winski and Albert Busch and Ekaterina Chernogubova and Francesca Fasolo and Zhiyuan Wu and Alexandra B{\"a}cklund and Khomtchouk, {Bohdan B.} and {van Booven}, {Derek J.} and Nadja Sachs and Hans-Henning Eckstein and Ilka Wittig and Boon, {Reinier A.} and Hong Jin and Lars Maegdefessel",
note = "Funding Information: This study is supported (all to L.M.) by the European Research Council (ERC-CoG project LongTx under the grant agreement number 101088370 ), a DZHK Translational Research Project (TRP), the SFB1123 and TRR267 of the German Research Council (DFG), the National Institutes of Health (NIH; 1R011HL150359-01 ), the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern, as well as Vetenkapsr{\aa}det ( 2019-01577 ), and Hj{\"a}rt-Lungfonden ( 20210450 ). B.B.K. acknowledges funding support from Indiana University and NIH R01DK132090 . Funding Information: The authors thank Marie-Luise Engl, Nadiya Glukha, Renate Hegenloh, and Changyan Sun for their technical assistance. This study is supported (all to L.M.) by the European Research Council (ERC-CoG project LongTx under the grant agreement number 101088370), a DZHK Translational Research Project (TRP), the SFB1123 and TRR267 of the German Research Council (DFG), the National Institutes of Health (NIH; 1R011HL150359-01), the Bavarian State Ministry of Health and Care through the research project DigiMed Bayern, as well as Vetenkapsr{\aa}det (2019-01577), and Hj{\"a}rt-Lungfonden (20210450). B.B.K. acknowledges funding support from Indiana University and NIH R01DK132090. H.W. F.F. H.J. and L.M. designed the research studies. H.W. G.W. A. Busch, E.C. F.F. A. B{\"a}cklund, and H.J. performed the experiments. Z.W. B.B.K. D.J.v.B. and I.W. acquired data. G.W. Z.W. B.B.K. D.J.v.B. I.W. and R.B. analyzed data and helped with data interpretation. N.S. and H.H.E. provided resources in the form of human specimens. H.W. H.J. and L.M. wrote the original draft of the manuscript. All authors reviewed and edited the manuscript. 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). Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = jun,
day = "7",
doi = "https://doi.org/10.1016/j.ymthe.2023.04.020",
language = "English",
volume = "31",
pages = "1775--1790",
journal = "Molecular therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "6",
}