Moderate to high concentrations of high-density lipoprotein from healthy subjects paradoxically impair human endothelial progenitor cells and related angiogenesis by activating rho-associated kinase pathways

Chun-Yao Huang, Feng-Yen Lin, Chun-Ming Shih, Heng-Kien Au, Yu-Jia Chang, Hironori Nakagami, Ryuichi Morishita, Nen-Chung Chang, Kou-Gi Shyu, Jaw Wen Chen

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

OBJECTIVE-: Recent clinical evidence has failed to demonstrate the benefits of elevation of serum high-density lipoprotein (HDL), suggesting potential loss of protective effects of HDL at high concentrations. This study aimed to investigate the concentration-related effects of HDL on in vitro and in vivo functions of human endothelial progenitor cells (EPCs) and related angiogenesis. METHODS AND RESULTS-: Early and late outgrowth EPCs were generated from human circulating mononuclear cells. Oxidized low-density lipoprotein reduced viability of late outgrowth EPCs, which was reversed dose dependently by HDL. In the absence of oxidized low-density lipoprotein, HDL at low concentrations (5-50 μg/mL, equal to 0.5-5 mg/dL in human) enhanced EPC tube formation by activating phosphatidylinositol-3 kinase/Akt/endothelial NO synthase pathways. Moderate to high concentrations (400-800 μg/mL) of HDL paradoxically enhanced EPC senescence and impaired tube formation by activating Rho-associated kinase (ROCK) and inhibiting phosphatidylinositol-3 kinase/Akt and p38 mitogen-activated protein kinase pathways. Rho-associated kinase inhibitors, either Y27632 or statins, prevented high HDL-induced EPC senescence and improved in vitro tube formation, as well as in vivo capacity of angiogenesis of EPCs. CONCLUSION-: While protecting EPCs from the injury of oxidized low-density lipoprotein, moderate to high concentrations of HDL paradoxically impaired EPCs and related angiogenesis in the absence of oxidized low-density lipoprotein by activating Rho-associated kinase pathways, providing mechanistic evidence of potential hazard effects of HDL.

Original languageEnglish
Pages (from-to)2405-2417
Number of pages13
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number10
DOIs
Publication statusPublished - Nov 2012

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Keywords

  • endothelial progenitor cells
  • high-density lipoprotein
  • Rho-associated protein kinase
  • senescence
  • statin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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