Allen S, Khan S, Al-Mohanna F, Batten P, Yacoub M
Department of Cardiothoracic Surgery, Imperial College of Science, Technology and Medicine, Harefield Hospital, Harefield, Middlesex, UB9 6JH United Kingdom.
J Clin Invest. 1998 Mar 1;101(5):1064-75. doi: 10.1172/JCI445.
Low density lipoprotein (LDL) interactions with the endothelium are thought to play a major role in the development of atherosclerosis. The mechanism(s) involved are not fully understood, although several lines of evidence support the idea that oxidation of LDL increases its atherogenicity. In this study we report for the first time that native LDL (n-LDL) binding to the LDL receptor (100-700 mug/ml) triggers a rise in intracellular calcium which acts as a second messenger to induce vascular cell adhesion molecule-1 (VCAM-1) expression in human coronary artery (HCAEC) and pig aortic endothelial cells (PAEC) and VCAM-1 and E-selectin expression in human aortic (HAEC) endothelial cells. Preincubation of HCAEC with a monoclonal antibody (IgGC7) to the classical LDL receptor or pretreatment with pertussis toxin blocked the n-LDL-induced calcium transients. Preincubation of each of the endothelial cell lines with the calcium chelator 1,-2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetic acetomethyl ester (BAPTA/AM) prevented the expression of VCAM-1 and E-selectin. The increase in VCAM-1 by n-LDL results in increased monocyte binding to HCAEC which can be attenuated by inhibiting the intracellular calcium rise or by blocking the VCAM-1 binding sites. These studies in human and pig endothelial cells link calcium signaling conferred by n-LDL to mechanisms controlling the expression of endothelial cell adhesion molecules involved in atherogenesis.
低密度脂蛋白（LDL）与内皮的相互作用被认为在动脉粥样硬化的发展中起主要作用。尽管有几条证据支持LDL氧化会增加其致动脉粥样硬化性的观点，但其中涉及的机制尚未完全明了。在本研究中，我们首次报告天然LDL（n-LDL）与LDL受体结合（100 - 700微克/毫升）会引发细胞内钙升高，钙作为第二信使可诱导人冠状动脉内皮细胞（HCAEC）和猪主动脉内皮细胞（PAEC）中血管细胞黏附分子-1（VCAM-1）的表达，以及人主动脉内皮细胞（HAEC）中VCAM-1和E-选择素的表达。用针对经典LDL受体的单克隆抗体（IgGC7）预孵育HCAEC或用百日咳毒素预处理可阻断n-LDL诱导的钙瞬变。用钙螯合剂1,2-双（邻氨基苯氧基）乙烷-N,N,N',N'-四乙酸乙酰甲酯（BAPTA/AM）预孵育每种内皮细胞系可防止VCAM-1和E-选择素的表达。n-LDL引起的VCAM-1增加导致单核细胞与HCAEC的结合增加，这可通过抑制细胞内钙升高或阻断VCAM-1结合位点来减弱。这些在人和猪内皮细胞中的研究将n-LDL赋予的钙信号传导与控制参与动脉粥样硬化形成的内皮细胞黏附分子表达的机制联系起来。
