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LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increased ubiquitination of thioredoxin-interacting protein

Abstract

Numerous studies have revealed that hyperglycemia is a pivotal driver of diabetic vascular complications. However, the mechanisms of hyperglycemia-induced endothelial dysfunction in diabetes remain incompletely understood. This study aims to expound on the underlying mechanism of the endothelial dysfunction induced by hyperglycemia from the perspective of long non-coding RNAs (lncRNA). In this study, a downregulation of SNHG15 was observed in the ischemic hind limb of diabetic mice and high glucose (HG)-treated HUVECs. Functionally, the overexpression of SNHG15 promoted cell proliferation, migration, and tube formation, and suppressed cell apoptosis in HG-treated HUVECs. Mechanistically, SNHG15 reduced thioredoxin-interacting protein (TXNIP) expression by enhancing ITCH-mediated ubiquitination of TXNIP. TXNIP overexpression abrogated the protective effect of lncRNA SNHG15 overexpression on HG-induced endothelial dysfunction. The following experiment further confirmed that SNHG15 overexpression promoted angiogenesis of the ischemic hind limb in diabetic mice. In conclusion, SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression.

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Fig. 1: The expression level of LncRNA SNHG15 in high glucose-treated HUVECs and ischemic hind limbs of diabetic mice.
Fig. 2: The effect of lncRNA SNHG15 overexpression on proliferation, migration, tube formation, and apoptosis of HG-treated HUVECs.
Fig. 3: SNHG15 interacted with thioredoxin-interacting protein (TXNIP) in HUVECs.
Fig. 4: SNHG15 downregulated TXNIP expression by promoting its ubiquitination.
Fig. 5: TXNIP mediated the regulatory effect of SNHG15 on proliferation, migration, tube formation, and apoptosis in HG-treated HUVECs.
Fig. 6: The effect of SNHG15 overexpression on angiogenesis in ischemic hind limbs of diabetic mice.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Major Science and Technology Project in Medical and Health of Zhejiang Province (co-constructed Project by Province and the Ministry, 2020380400, WKJ-ZJ-2003) and the Key Program of Natural Science Foundation of Zhejiang Province (LZ21H020001).

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Dong-lin Li and Hong-kun Zhang performed development of methodology and writing, review and revision of the paper; Tian-chi Chen, Xun Wang, and Lu Tian performed investigation; Zi-heng Wu, Xiao-hui Wang, Yun-yun He, and Yang-yan He provided visualization and supervision; Tao Shang and Yi-lang Xiang performed writing-reviewing and editing; Qian-qian Zhu and Ming-chun Lai contributed to the conception of the study, performed the experiments and wrote the paper.

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Correspondence to Dong-lin Li or Hong-kun Zhang.

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The authors declare no competing interests.

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All animal experiments were approved by the Ethics Committee of the The First Affiliated Hospital, School of Medicine, Zhejiang University.

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Zhu, Qq., Lai, Mc., Chen, Tc. et al. LncRNA SNHG15 relieves hyperglycemia-induced endothelial dysfunction via increased ubiquitination of thioredoxin-interacting protein. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00614-5

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