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

研究成果: 雜誌貢獻文章

33 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)2405-2417
頁數13
期刊Arteriosclerosis, Thrombosis, and Vascular Biology
32
發行號10
DOIs
出版狀態已發佈 - 十一月 2012

指紋

rho-Associated Kinases
HDL Lipoproteins
Healthy Volunteers
Phosphatidylinositol 3-Kinase
Cell Aging
Endothelial Progenitor Cells
Hydroxymethylglutaryl-CoA Reductase Inhibitors
p38 Mitogen-Activated Protein Kinases
Nitric Oxide Synthase
oxidized low density lipoprotein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

引用此文

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title = "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",
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.",
keywords = "endothelial progenitor cells, high-density lipoprotein, Rho-associated protein kinase, senescence, statin",
author = "Chun-Yao Huang and Feng-Yen Lin and Chun-Ming Shih and Heng-Kien Au and Yu-Jia Chang and Hironori Nakagami and Ryuichi Morishita and Nen-Chung Chang and Kou-Gi Shyu and Chen, {Jaw Wen}",
year = "2012",
month = "11",
doi = "10.1161/ATVBAHA.112.248617",
language = "English",
volume = "32",
pages = "2405--2417",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "10",

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TY - JOUR

T1 - 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

AU - Huang, Chun-Yao

AU - Lin, Feng-Yen

AU - Shih, Chun-Ming

AU - Au, Heng-Kien

AU - Chang, Yu-Jia

AU - Nakagami, Hironori

AU - Morishita, Ryuichi

AU - Chang, Nen-Chung

AU - Shyu, Kou-Gi

AU - Chen, Jaw Wen

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

KW - endothelial progenitor cells

KW - high-density lipoprotein

KW - Rho-associated protein kinase

KW - senescence

KW - statin

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U2 - 10.1161/ATVBAHA.112.248617

DO - 10.1161/ATVBAHA.112.248617

M3 - Article

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VL - 32

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JO - Arteriosclerosis, Thrombosis, and Vascular Biology

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