Cytotoxic phospholipid oxidation products - Cell death from mitochondrial damage and the intrinsic caspase cascade
Cytotoxic phospholipid oxidation products - Cell death from mitochondrial damage and the intrinsic caspase cascade
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DOI：
10.1074/jbc.m702865200
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发表时间：
2007-08-24
影响因子：
4.8
通讯作者：
McIntyre, Thomas M.
中科院分区：
文献类型：
--
作者：
Chen, Rui;Yang, Lili;McIntyre, Thomas M.
磷脂氧化产物在动脉粥样硬化病变的坏死核心、凋亡细胞中积累，并在氧化低密度脂蛋白中循环。磷脂氧化产生有毒产物，但对哪些特定产物具有细胞毒性、其受体或诱导细胞死亡的机制知之甚少。我们发现最常见的氧化低密度脂蛋白的磷脂氧化产物，磷脂酰胆碱与酯化的sn-2-壬二酸，在低微摩尔浓度诱导细胞凋亡。合成的醚磷脂十六烷基壬二酰磷脂酰胆碱（HAzPC）被迅速内化，PLA 2g 7（PAF乙酰水解酶），特异性水解这种氧化磷脂抑制细胞凋亡的过表达。在暴露于HAzPC的细胞中，与线粒体相关的内化HAzPC、细胞色素c和凋亡诱导因子分别从线粒体逃逸到细胞质和细胞核。孤立的线粒体暴露于HAzPC迅速膨胀，并释放细胞色素c和凋亡诱导因子。其他磷脂氧化产物诱导肿胀，但HAzPC是最有效的，是其二酰基同系物的两倍。细胞质细胞色素c完成的溶酶体，和激活的半胱天冬酶9和3存在于暴露于HAzPC的细胞。caspase 9的不可逆抑制阻断了下游caspase 3的激活并阻止了细胞凋亡。线粒体损伤启动了这种凋亡级联反应，因为Bcl-X-L（一种定位于线粒体的抗凋亡蛋白）的过表达阻断了细胞色素c逃逸和凋亡。因此，外源性磷脂氧化产物靶向细胞内线粒体以激活内在凋亡级联。
Phospholipid oxidation products accumulate in the necrotic core of atherosclerotic lesions, in apoptotic cells, and circulate in oxidized low density lipoprotein. Phospholipid oxidation generates toxic products, but little is known about which specific products are cytotoxic, their receptors, or the mechanism(s) that induces cell death. We find the most common phospholipid oxidation product of oxidized low density lipoprotein, phosphatidylcholine with esterified sn-2-azelaic acid, induced apoptosis at low micromolar concentrations. The synthetic ether phospholipid hexadecyl azelaoyl phosphatidylcholine (HAzPC) was rapidly internalized, and overexpression of PLA2g7 (PAF acetylhydrolase) that specifically hydrolyzes such oxidized phospholipids suppressed apoptosis. Internalized HAzPC associated with mitochondria, and cytochrome c, and apoptosis-inducing factor escaped from mitochondria to the cytoplasm and nucleus, respectively, in cells exposed to HAzPC. Isolated mitochondria exposed to HAzPC rapidly swelled and released cytochrome c and apoptosis-inducing factor. Other phospholipid oxidation products induced swelling, but HAzPC was the most effective and was twice as effective as its diacyl homolog. Cytoplasmic cytochrome c completes the apoptosome, and activated caspase 9 and 3 were present in cells exposed to HAzPC. Irreversible inhibition of caspase 9 blocked downstream caspase 3 activation and prevented apoptosis. Mitochondrial damage initiated this apoptotic cascade, because overexpression of Bcl-X-L, an anti-apoptotic protein localized to mitochondria, blocked cytochrome c escape and apoptosis. Thus, exogenous phospholipid oxidation products target intracellular mitochondria to activate the intrinsic apoptotic cascade.