TY  - JOUR
A1  - Winter, Hanna
A1  - Winski, Greg
A1  - Busch, Albert Franz Jakob
A1  - Chernogubova, Ekaterina
A1  - Fasolo, Francesca
A1  - Wu, Zhiyuan
A1  - Bäcklund, Alexandra
A1  - Khomtchouk, Bohdan B.
A1  - Van Booven, Derek J.
A1  - Sachs, Nadja
A1  - Eckstein, Hans-Henning
A1  - Wittig, Ilka
A1  - Boon, Reinier
A1  - Jin, Hong
A1  - Mägdefessel, Lars
T1  - Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression
T2  - Molecular therapy
N2  - 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.
KW  - long non-coding RNAs
KW  - atherosclerosis
KW  - aortic aneurysm
KW  - smooth muscle cell
KW  - proliferation
KW  - vascular disease
KW  - therapeutics
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78980
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-789804
SN  - 1525-0016
VL  - 31
IS  - 6
SP  - 1775
EP  - 1790
PB  - Elsevier
CY  - Amsterdam
ER  -