Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids - Implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages
Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids - Implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages
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DOI：
10.1074/jbc.m405195200
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发表时间：
2004-08-27
影响因子：
4.8
通讯作者：
Tabas, I
中科院分区：
文献类型：
--
作者：
Li, YK;Ge, MT;Tabas, I
晚期动脉粥样硬化病变中的巨噬细胞积累大量未酯化或“游离”胆固醇（FC）。FC积累诱导巨噬细胞凋亡，这可能有助于斑块的不稳定。细胞凋亡是由富含FC的内质网（ER）引发的，导致内质网钙储存的消耗，并诱导未折叠蛋白反应。为了解释内质网钙消耗的机制，我们假设正常情况下胆固醇含量较低的内质网膜的FC富集抑制巨噬细胞内质网钙泵、肌浆-内质网钙atp -2b （SERCA2b）。ER膜的FC富集到与体内相似的水平，抑制了SERCA2b的atp酶活性和钙固存功能。内质网富集ent-胆固醇或14:0-18:0磷脂酰胆碱，具有胆固醇的膜排序特性，也抑制SERCA2b。此外，在不同水平的FC富集ER膜时，16-羟-磷脂酰胆碱电子自旋共振监测的膜脂序增加与SERCA2b抑制之间存在非常密切的相关性。鉴于这些数据，我们推测SERCA2b是一种构象活性蛋白，具有11个跨膜区域，由于在fc有序膜中构象自由度降低而失去功能。这种生物物理模型可能是晚期动脉粥样硬化中过量胆固醇、未折叠蛋白反应诱导、巨噬细胞死亡和斑块不稳定之间的关键联系的基础。
Macrophages in advanced atherosclerotic lesions accumulate large amounts of unesterified, or "free," cholesterol (FC). FC accumulation induces macrophage apoptosis, which likely contributes to plaque destabilization. Apoptosis is triggered by the enrichment of the endoplasmic reticulum (ER) with FC, resulting in depletion of ER calcium stores, and induction of the unfolded protein response. To explain the mechanism of ER calcium depletion, we hypothesized that FC enrichment of the normally cholesterol-poor ER membrane inhibits the macrophage ER calcium pump, sarcoplasmic-endoplasmic reticulum calcium ATPase-2b (SERCA2b). FC enrichment of ER membranes to a level similar to that occuring in vivo inhibited both the ATPase activity and calcium sequestration function of SERCA2b. Enrichment of ER with ent-cholesterol or 14:0-18:0 phosphatidylcholine, which possess the membrane-ordering properties of cholesterol, also inhibited SERCA2b. Moreover, at various levels of FC enrichment of ER membranes, there was a very close correlation between increasing membrane lipid order, as monitored by 16-doxyl-phosphatidycholine electron spin resonance, and SERCA2b inhibition. In view of these data, we speculate that SERCA2b, a conformationally active protein with 11 membrane-spanning regions, loses function due to decreased conformational freedom in FC-ordered membranes. This biophysical model may underlie the critical connection between excess cholesterol, unfolded protein response induction, macrophage death, and plaque destabilization in advanced atherosclerosis.