Dysfunctional high density lipoprotein failed to rescue the function of oxidized low density lipoprotein-treated endothelial progenitor cells: a novel index for the prediction of HDL functionality

• Published in: Translational Research Vol. 205; pp. 17 - 32
• Main Authors: Shih, Chun-Ming, Lin, Feng-Yen, Yeh, Jong-Shiuan, Lin, Yi-Wen, Loh, Shih-Hurng, Tsao, Nai-Wen, Nakagami, Hironori, Morishita, Ryuichi, Sawamura, Tatsuya, Li, Chi-Yuan, Lin, Cheng-Yen, Huang, Chun-Yao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; Elsevier BV
• Subjects: ACS = acute coronary syndrome; Adult; Aged; ALT= alanine transaminase; APOI = apocynin; CAD = coronary artery disease; CETP = cholesterol ester transfer protein; DCFH-DA = 2′,7′-dichlorofluorescin diacetate; Dyslipidemias; Endothelial Progenitor Cells; eNOS = endothelial nitric oxide synthase; Enzyme Activation; Female; HDL = high density lipoprotein; HPODE = hydroperoxyoctadeca-9Z,11E-dienoic acid; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Lipoxygenase; Male; Middle Aged; MNC = mononuclear cell; Nitric Oxide; NO = nitric oxide; p38 Mitogen-Activated Protein Kinases; PAH-AH = platelet-activating factor acetylhydrolase; PMA = phorbol 12-myristate 13-acetate; PON1 = paraoxonase-1; RHDL index = relative HDL index; rho-Associated Kinases; Signal Transduction; TBARS = thiobarbituric acid reactive substance; TC = total cholesterol; TG = triglycerides; HDL = high density lipoprotein; PON1 = paraoxonase-1; TBARS = thiobarbituric acid reactive substance; DCFH-DA = 2′,7′-dichlorofluorescin diacetate; HPODE = hydroperoxyoctadeca-9Z,11E-dienoic acid; TG = triglycerides; PMA = phorbol 12-myristate 13-acetate; eNOS = endothelial nitric oxide synthase; CETP = cholesterol ester transfer protein; RHDL index = relative HDL index; TC = total cholesterol; MNC = mononuclear cell; APOI = apocynin; NO = nitric oxide; ACS = acute coronary syndrome; ALT= alanine transaminase; PAH-AH = platelet-activating factor acetylhydrolase; CAD = coronary artery disease
• DOI: 10.1016/j.trsl.2018.09.005
• ISSN: 1931-5244; 1878-1810

Lipid metabolic disorders play critical roles in atherogenesis. Traditionally, it has been suggested that reduced high density lipoprotein (HDL) levels might be an important morbidity indicator for cardiovascular diseases. Therefore, it has been argued that therapeutically raising HDL levels may reduce atherogenesis in patients with dyslipidemia. However, recent clinical trials to elevate serum HDL levels by pharmacologic approaches failed to demonstrate clinical efficacy. Thus, to investigate the functionality of HDL and to explore the possible clinical relevance as well as to define an effective indicator that can represent HDL function may provide another key and reference to disclose the clinical treatment of dyslipidemia. We analyzed the association between the data of dichlorofluorescein assay (assay the functionality of HDL), the effect of HDL on oxidized low density lipoprotein (oxLDL)-stimulated endothelial progenitor cells (EPCs) in vitro, levels of circulating EPCs, and ex vitro EPC colony forming units of each case, we defined the indicator (relative HDL index (RHDL index) = dichlorofluorescein assay result of each subject/dichlorofluorescein assay reading of our young healthy controls) that may represent functionality of HDL. HDL from healthy adults protected oxLDL-treated EPCs by modulating p38 mitogen-activated protein kinase and Rho activation and by promoting nitric oxide production. HDL from subject with RHDL index ≧2 also failed to restore the functionality of oxLDL-treated EPCs via cell-signaling pathways in vitro. The RHDL index significantly correlated with patients’ circulating EPC number or EPC colony forming units ex vivo. In conclusions, we explored the RHDL index as a score to predict a patient's EPC functions in vivo and ex vitro.