ESC Heart Failure (Aug 2022)

LncRNA HOXA11‐AS promotes vascular endothelial cell injury in atherosclerosis by regulating the miR‐515‐5p/ROCK1 axis

  • Feng Gao,
  • Xiao‐Chen Wang,
  • Zhi‐Dan Luo,
  • Guang‐Quan Hu,
  • Meng‐Qing Ma,
  • Yi Liang,
  • Bang‐Long Xu,
  • Xian‐He Lin

DOI
https://doi.org/10.1002/ehf2.13815
Journal volume & issue
Vol. 9, no. 4
pp. 2259 – 2271

Abstract

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Abstract Aims Long non‐coding RNA HOXA11‐AS participated in heart disease. In this study, we aim to evaluate the potential roles of HOXA11‐AS in atherosclerosis and its underlying mechanisms. Methods and results The expression levels of HOXA11‐AS in ox‐LDL‐treated HUVECs and arch tissues of high‐fat diet‐fed ApoE−/− mice (n = 10) were assessed by qRT‐PCR. The effects of HOXA11‐AS knockdown on the development of atherosclerosis were evaluated using in vitro and in vivo models. Luciferase reporter and RNA immunoprecipitation (RIP) assays verified the potential relationships between HOXA11‐AS or ROCK1 and miR‐515‐5p. The interactive roles between HOXA11‐AS and miR‐515‐5p and between miR‐515‐5p and ROCK1 were further characterized in ox‐LDL‐treated HUVECs. Our data showed that HOXA11‐AS was significantly up‐regulated (P < 0.001), whereas miR‐515‐5p was dramatically down‐regulated in AS mice tissues (P < 0.001) and ox‐LDL‐treated HUVECs (P < 0.01). Ox‐LDL could induce endothelial injuries by inhibiting cell proliferation (P < 0.001) and SOD synthesis (P < 0.001), promoting apoptosis (P < 0.01), ROS (P < 0.001), and MDA production (P < 0.001), increasing Bax (P < 0.001) and cleaved Caspase‐3 (P < 0.001), and decreasing Bcl‐2 (P < 0.001) and phosphorylated eNOS (P < 0.01). HOXA11‐AS knockdown attenuated endothelial injuries via increasing eNOS phosphorylation. Luciferase assay and RIP results confirmed that miR‐515‐5p is directly bound to HOXA11‐AS and ROCK1. HOXA11‐AS promoted ox‐LDL‐induced HUVECs injury by directly inhibiting miR‐515‐5p from increasing ROCK1 expression and subsequently decreasing the expression and phosphorylation of eNOS. MiR‐515‐5p mimics could partially reverse the effects of HOXA11‐AS knockdown. Conclusions HOXA11‐AS contributed to atherosclerotic injuries by directly regulating the miR‐515‐5p/ROCK1 axis. This study provided new evidence that HOXA11‐AS might be a candidate for atherosclerosis therapy.

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