Chang Chiz-Tzung, Wang Guei-Jane, Kuo Chin-Chi, Hsieh Ju-Yi, Lee An-Sean, Chang Chia-Ming, Wang Chun-Cheng, Shen Ming-Yi, Huang Chiu-Ching, Sawamura Tatsuya, Yang Chao-Yuh, Stancel Nicole, Chen Chu-Huang
From the L5 Research Center, China Medical University (CMU) Hospital (C-TC, J-YH, A-SL, C-MC, M-YS, C-YY, C-HC); Division of Nephrology, CMU Hospital (C-TC, C-CK, C-CH); College of Medicine, CMU (C-TC, C-CK); Graduate Institute of Clinical Medical Science, CMU (G-JW, C-CW, M-YS); Department of Health and Nutrition Biotechnology, Asia University (G-JW), Taichung, Taiwan; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA (C-CK); Department of Medicine, Mackay Medical College, New Taipei, Taiwan (A-SL); Department of Physiology, Shinshu University School of Medicine, Matsumoto, Nagono, Japan (TS); Vascular and Medicinal Research, Texas Heart Institute, Houston, Texas, USA (NS, C-HC); Lipid Science and Aging Research Center, Kaohsiung Medical University (KMU) (C-HC); Center for Lipid Biosciences, KMU Hospital, KMU, Kaohsiung (C-HC); New York Heart Research Foundation, Mineola, New York, USA (C-HC); and Lipid and Glycoimmune Research Center, Changhua Christian Hospital, Changhua, Taiwan (C-HC).
Medicine (Baltimore). 2016 Jan;95(2):e2265. doi: 10.1097/MD.0000000000002265.
Electronegative low-density lipoprotein (LDL) is a recognized factor in the pathogenesis of coronary artery disease (CAD) in the general population, but its role in the development of CAD in uremia patients is unknown. L5 is the most electronegative subfraction of LDL isolated from human plasma. In this study, we examined the distribution of L5 (L5%) and its association with CAD risk in uremia patients.The LDL of 39 uremia patients on maintenance hemodialysis and 21 healthy controls was separated into 5 subfractions, L1-L5, with increasing electronegativity. We compared the distribution and composition of plasma L5 between uremia patients and controls, examined the association between plasma L5% and CAD risk in uremia patients, and studied the effects of L5 from uremia patients on endothelial function.Compared to controls, uremia patients had significantly increased L5% (P < 0.001) and L5 that was rich in apolipoprotein C3 and triglycerides. L5% was significantly higher in uremia patients with CAD (n = 10) than in those without CAD (n = 29) (P < 0.05). Independent of other major CAD risk factors, the adjusted odds ratio for CAD was 1.88 per percent increase in plasma L5% (95% CI, 1.01-3.53), with a near-linear dose-response relationship. Compared with controls, uremia patients had decreased flow-mediated vascular dilatation. In ex vivo studies with preconstricted rat thoracic aortic rings, L5 from uremia patients inhibited acetylcholine-induced relaxation. In cultured human endothelial cells, L5 inhibited endothelial nitric oxide synthase activation and induced endothelial dysfunction.Our findings suggest that elevated plasma L5% may induce endothelial dysfunction and play an important role in the increased risk of CAD in uremia patients.
在普通人群中，带负电的低密度脂蛋白（LDL）是冠状动脉疾病（CAD）发病机制中的一个公认因素，但其在尿毒症患者CAD发生发展中的作用尚不清楚。L5是从人血浆中分离出的LDL中带负电最强的亚组分。在本研究中，我们检测了尿毒症患者中L5的分布情况（L5%）及其与CAD风险的关系。将39例维持性血液透析的尿毒症患者和21例健康对照者的LDL分离为5个亚组分，即L1 - L5，其负电性逐渐增强。我们比较了尿毒症患者和对照者血浆L5的分布及组成，检测了尿毒症患者血浆L5%与CAD风险的关系，并研究了尿毒症患者的L5对内皮功能的影响。与对照者相比，尿毒症患者的L5%显著升高（P < 0.001），且L5富含载脂蛋白C3和甘油三酯。患有CAD的尿毒症患者（n = 10）的L5%显著高于未患CAD的患者（n = 29）（P < 0.05）。独立于其他主要CAD危险因素，血浆L5%每增加1%，CAD的校正比值比为1.88（95%可信区间，1.01 - 3.53），呈近似线性剂量反应关系。与对照者相比，尿毒症患者的血流介导的血管扩张减弱。在对预先收缩的大鼠胸主动脉环进行的体外研究中，尿毒症患者的L5抑制乙酰胆碱诱导的舒张。在培养的人内皮细胞中，L5抑制内皮型一氧化氮合酶的激活并诱导内皮功能障碍。我们的研究结果表明，血浆L5%升高可能诱导内皮功能障碍，并在尿毒症患者CAD风险增加中起重要作用。
