Signal Transduction and Targeted Therapy (Aug 2023)

High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA

  • Zhi-Wei Mo,
  • Yue-Ming Peng,
  • Yi-Xin Zhang,
  • Yan Li,
  • Bi-Ang Kang,
  • Ya-Ting Chen,
  • Le Li,
  • Mary G. Sorci-Thomas,
  • Yi-Jun Lin,
  • Yang Cao,
  • Si Chen,
  • Ze-Long Liu,
  • Jian-Jun Gao,
  • Zhan-Peng Huang,
  • Jia-Guo Zhou,
  • Mian Wang,
  • Guang-Qi Chang,
  • Meng-Jie Deng,
  • Yu-Jia Liu,
  • Zhen-Sheng Ma,
  • Zuo-Jun Hu,
  • Yu-Gang Dong,
  • Zhi-Jun Ou,
  • Jing-Song Ou

DOI
https://doi.org/10.1038/s41392-023-01558-6
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 18

Abstract

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Abstract Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.