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bioRxiv · 10.1101/2023.04.21.537806

Notch regulated long non-coding RNA TUG1 regulates smooth muscle cell differentiation in aortic aneurysm

Kumarswamy, R.·Ravi, A. B.
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Abstract

Abdominal Aortic Aneurysms (AAAs) are asymptomatic vascular diseases with life threatening outcomes. Smooth-muscle cell (SMC) dysfunction plays an important role in AAA development. The contributions of non-coding genome, specifically the role of long non-coding RNAs (lncRNAs) in SMC dysfunction are relatively unexplored. We investigated the role of lncRNA TUG1 in the pathology of AAA. TUG1 was identified through lncRNA profiling in Angiotensin-II (Ang-II) treated SMCs. TUG1 was upregulated in Ang-II treated SMCs in vitro and its expression increased with progression of aneurysm in mouse model of Ang-II induced AAA. Ang-II induced TUG1 was blunted by inhibition of Notch signaling and TUG1 is demonstrated to be a transcriptional target of Notch. AAA tissues exhibited inversely correlated expression of TUG1 and SMC contractile markers. TUG1 knock-down via siRNA/shRNA increased SMC differentiation. ChIP, DNA-RNA IP, and RNA-IP experiments demonstrated that TUG1 interacts with transcriptional repressor KLF4 and aides in its recruitment to Myocardin promoter, thereby repressing SMC differentiation. In summary, we show a novel role for lncRNA TUG1 in Ang-II induced AAA wherein it modulates SMC differentiation via KLF4-Myocardin axis.

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Kumarswamy, R., Ravi, A. B.. 2023-04-21. Notch regulated long non-coding RNA TUG1 regulates smooth muscle cell differentiation in aortic aneurysm. https://doi.org/10.1101/2023.04.21.537806

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