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

Winter, H.; Winski, G.; Busch, A.; Chernogubova, E.; Fasolo, F.; Wu, Z.; Backlund, A.; Khomtchouk, B. B.; Van Booven, D.; Sachs, N.; Eckstein, H.-H.; Wittig, I.; Boon, R. A.; Jin, H.; Maegdefessel, L.

doi:10.1101/2022.11.14.516372

bioRxiv · 10.1101/2022.11.14.516372

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

Winter, H.·Winski, G.·Busch, A.·Chernogubova, E.·Fasolo, F.·Wu, Z.·Backlund, A.·Khomtchouk, B. B.·Van Booven, D.·Sachs, N.·Eckstein, H.-H.·Wittig, I.·Boon, R. A.·Jin, H.·Maegdefessel, L.

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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 models 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.

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Winter, H., Winski, G., Busch, A., Chernogubova, E., Fasolo, F., Wu, Z., Backlund, A., Khomtchouk, B. B., Van Booven, D., Sachs, N., Eckstein, H.-H., Wittig, I., Boon, R. A., Jin, H., Maegdefessel, L.. 2022-11-15. Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression. https://doi.org/10.1101/2022.11.14.516372

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