Ali Kamilah, Lund-Katz Sissel, Lawson John, Phillips Michael C, Rader Daniel J
Institute for Translational Medicine and Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
Atherosclerosis. 2008 Jan;196(1):201-209. doi: 10.1016/j.atherosclerosis.2007.03.038. Epub 2007 May 25.
Apolipoprotein (apoE) E is a multifunctional protein that plays a critical role in atherogenesis, in part by regulating the intimal proliferation of vascular smooth muscle cells. Recently, a novel cyclooxygenase (COX)-2 pathway was shown to contribute to the anti-proliferative action of human apoE3 in vascular smooth muscle cells (VSMC). Here, we provide insight into the structure-function properties by which apoE mediates these effects. ApoE3 is most effective in promoting COX-2 expression as a lipid-free protein and is less active after lipidation. Alterations in the stability of the helix bundle N-terminal domain of apoE that contains the binding site for the low density lipoprotein (LDL) receptor and heparin do not affect the up-regulation of the COX-2 pathway. In addition, the apoE2, 3, and 4 isoforms are all capable of up-regulating the COX-2 pathway. Finally, the effect of apoE on COX-2 was found to be independent of expression on the VSMC surface of the LDL receptor and heparan sulfate proteoglycans (HSPG). In summary, our data indicates that apoE, particularly in the lipid-free state, can up-regulate COX-2 in murine vascular smooth muscle cells apparently independently of binding to the LDLR, LRP or HSPG.
载脂蛋白（apoE）E是一种多功能蛋白质，在动脉粥样硬化形成过程中发挥关键作用，部分原因是通过调节血管平滑肌细胞的内膜增殖。最近，一种新的环氧化酶（COX）-2途径被证明有助于人apoE3在血管平滑肌细胞（VSMC）中的抗增殖作用。在此，我们深入了解了apoE介导这些效应的结构-功能特性。apoE3作为无脂蛋白质在促进COX-2表达方面最有效，脂化后活性降低。apoE螺旋束N端结构域的稳定性发生改变，该结构域包含低密度脂蛋白（LDL）受体和肝素的结合位点，但不影响COX-2途径的上调。此外，apoE2、3和4异构体均能够上调COX-2途径。最后，发现apoE对COX-2的作用独立于LDL受体和硫酸乙酰肝素蛋白聚糖（HSPG）在VSMC表面的表达。总之，我们的数据表明，apoE，特别是在无脂状态下，能够在小鼠血管平滑肌细胞中上调COX-2，显然独立于与LDLR、LRP或HSPG的结合。
