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

Qian-Qian Zhu; Ming-Chun Lai; Tian-Chi Chen; Xun Wang; Lu Tian; Dong-Lin Li; Zi-Heng Wu; Xiao-Hui Wang; Yun-Yun He; Yang-Yan He; Tao Shang; Yi-Lang Xiang; Hong-Kun Zhang

doi:10.1016/j.lfs.2021.119255

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

Life Sci. 2021 Feb 23:119255. doi: 10.1016/j.lfs.2021.119255. Online ahead of print.

Authors

Affiliations

¹ Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
² Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
³ Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: donglin_Li0616@126.com.
⁴ Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China. Electronic address: 1198050@zju.edu.cn.

PMID: 33636173
DOI: 10.1016/j.lfs.2021.119255

Abstract

Objective: Numerous evidence indicates that hyperglycemia is a pivotal driver of the vascular complications of diabetes. 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).

Materials and methods: Cell proliferation, migration, apoptosis, and tube formation were measured by cell counting kit-8 assay, transwell assay, flow cytometry, and tube formation assay, respectively. RNA pull-down and RNA-binding protein immunoprecipitation were used to detect the interaction between lncRNA SNHG15 and thioredoxin-interacting protein (TXNIP). Co-immunoprecipitation was used to detect the ubiquitination level of TXNIP and the interaction between TXNIP and E3 ubiquitin ligase ITCH.

Results: 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. Mechanically, SNHG15 reduced 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.

Conclusion: SNHG15 is a novel protector for hyperglycemia-induced endothelial dysfunction via decreasing TXNIP expression.

Keywords: Diabetes; Endothelial dysfunction; Hyperglycemia; LncRNA SNHG15; Thioredoxin-interacting protein.