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

• Published in: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32; no. 10; pp. 2405 - 2417
• Main Authors: Huang, Chun-Yao, Lin, Feng-Yen, Shih, Chun-Ming, Au, Heng-Kien, Chang, Yu-Jia, Nakagami, Hironori, Morishita, Ryuichi, Chang, Nen-Chung, Shyu, Kou-Gi, Chen, Jaw-Wen
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Ovid Technologies (Wolters Kluwer Health) 01.10.2012; American Heart Association, Inc; Lippincott Williams & Wilkins
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cell Survival; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Cellular Senescence; Cellular Senescence - drug effects; Cellular Senescence - physiology; Diabetes Mellitus; Diabetes Mellitus - metabolism; Diabetes Mellitus - physiopathology; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Endothelium, Vascular; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Fundamental and applied biological sciences. Psychology; Humans; In Vitro Techniques; Lipoproteins, HDL; Lipoproteins, HDL - pharmacology; Lipoproteins, LDL; Lipoproteins, LDL - pharmacology; Male; Medical sciences; Mice; Mice, SCID; Neovascularization, Physiologic; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Nitric Oxide; Nitric Oxide - metabolism; p38 Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases - drug effects; p38 Mitogen-Activated Protein Kinases - physiology; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - physiology; rho-Associated Kinases; rho-Associated Kinases - drug effects; rho-Associated Kinases - physiology; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Stem Cells; Stem Cells - cytology; Stem Cells - drug effects; Vertebrates: cardiovascular system; Young Adult; Human; Endothelial cell; Senescence; Enzyme; Transferases; Non-specific serine/threonine protein kinase; high-density lipoprotein; Cardiovascular disease; Statin derivative; Rho-associated protein kinase; Lipoprotein; Vascular disease; Angiogenesis; statin; endothelial progenitor cells; Atherosclerosis; Progenitor cell; Antilipemic agent
• DOI: 10.1161/atvbaha.112.248617
• ISSN: 1079-5642; 1524-4636

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.