High-density lipoproteins augment hypoxia-induced angiogenesis via regulation of post-translational modulation of hypoxia-inducible factor 1α

Joanne T.M. Tan, Hamish C. Hamish, Laura Z. Vanags, Steven A. Monger, Martin K.C. Ng, Christina A. Bursill

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Increasing evidence suggests that highdensity lipoproteins (HDLs) promote hypoxia-induced angiogenesis. The hypoxia-inducible factor 1α (HIF- 1α)/vascular endothelial growth factor (VEGF) pathway is important in hypoxia and is modulated posttranslationally by prolyl hydroxylases (PHD1-PHD3) and E3 ubiquitin ligases (Siah1 and Siah2). We aimed to elucidate the mechanisms by which HDLs augment hypoxia-induced angiogenesis. Preincubation (16 h) of human coronary artery endothelial cells with reconstituted high-density lipoprotein (rHDL) containing apolipoprotein A-I (apoA-I) and phosphatidylcholine (20 μM, final apoA-I concentration), before hypoxia, increased Siah1 (58%) and Siah2 (88%) mRNA levels and suppressed PHD2 (32%) and PHD3 (45%) protein levels compared with hypoxia-induced control levels. After Siah1/2 small interfering RNA knockdown, rHDL was unable to suppress PHD2/3 and failed to induce HIF-1α, VEGF, and tubulogenesis in hypoxia. Inhibition of the upstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway also abrogated the effects of rHDL. Furthermore, knockdown of the scavenger receptor SR-BI attenuated rHDL-induced elevations in Siah1/2 and tubulogenesis in hypoxia, indicating that SR-BI plays a key role. Finally, the importance of VEGF in mediating the ability of rHDL to drive hypoxia-induced angiogenesis was confirmed using a VEGF-neutralizing antibody. In summary, rHDL augments the HIF-1α/VEGF pathway via SR-BI and modulation of the post-translational regulators of HIF-1α (PI3K/Siahs/PHDs). HDL-induced augmentation of angiogenesis in hypoxia may have implications for therapeutic modulation of ischemic injury.

Original languageEnglish
Pages (from-to)206-217
Number of pages12
JournalFASEB Journal
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2014
Externally publishedYes

Keywords

  • Endothelial cells
  • PI3K/Akt pathway
  • Phosphatidylinositol 3-kinase
  • Prolyl hydroxylase domain proteins
  • Scavenger receptor BI
  • Siah ubiquitin ligases

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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