Tanel André, Averill-Bates Diana A
Département des Sciences Biologiques, TOXEN, Université du Québec à Montréal, CP 8888, Succursale Centre Ville, Montréal, QC, Canada.
Free Radic Biol Med. 2007 Mar 15;42(6):798-810. doi: 10.1016/j.freeradbiomed.2006.12.009. Epub 2006 Dec 14.
Reactive alpha,beta-unsaturated aldehydes such as acrolein are major components of common environmental pollutants. As a toxic by-product of lipid peroxidation, acrolein has been implicated as a possible mediator of oxidative damage to cells and tissues in a wide variety of disease states, including atherosclerosis and neurodegenerative and pulmonary diseases. Although acrolein can induce apoptotic cell death in various cell types, the biochemical mechanisms are not understood. This study investigates the implication of the death receptor pathway in acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to acrolein caused translocation of adaptor protein Fas associated with death domain to the cytoplasmic membrane and caspase-8 activation. Kp7-6, an antagonist of Fas receptor activation, blocked apoptotic events downstream of caspase-8, such as caspase-7 activation and nuclear chromatin condensation. Acrolein activated the cross-talk pathway between the death receptor and mitochondrial pathways. Bid was cleaved to truncated-Bid, which was translocated to mitochondria. Activation of the mitochondrial pathway by acrolein was confirmed by caspase-9 activation. Inhibition of activation of either the Fas receptor or caspase-8 partially decreased acrolein-induced caspase-9 activation. These findings indicate that acrolein activates the Fas receptor pathway, which occurs upstream of the mitochondrial pathway. Caspase-9 activation still occurred despite inhibition of the Fas receptor pathway, suggesting that acrolein could also trigger the mitochondrial pathway independent of the receptor pathway. These findings improve our understanding of mechanisms of toxicity of the reactive aldehyde acrolein, which has widespread implications in multiple disease states which seem to be mediated by oxidative stress and lipid peroxidation.
反应性α,β-不饱和醛（如丙烯醛）是常见环境污染物的主要成分。作为脂质过氧化的有毒副产物，丙烯醛被认为是多种疾病状态下细胞和组织氧化损伤的可能介质，包括动脉粥样硬化、神经退行性疾病和肺部疾病。尽管丙烯醛可诱导多种细胞类型发生凋亡性细胞死亡，但其生化机制尚不清楚。本研究调查了死亡受体途径在丙烯醛诱导的凋亡中的作用。将中国仓鼠卵巢细胞暴露于丙烯醛会导致死亡结构域相关衔接蛋白Fas向细胞质膜转位并激活半胱天冬酶-8。Fas受体激活拮抗剂Kp7-6可阻断半胱天冬酶-8下游的凋亡事件，如半胱天冬酶-7激活和核染色质凝聚。丙烯醛激活了死亡受体途径和线粒体途径之间的串扰途径。Bid被切割成截短的Bid，并转位至线粒体。丙烯醛通过激活半胱天冬酶-9证实了其对线粒体途径的激活作用。抑制Fas受体或半胱天冬酶-8的激活可部分降低丙烯醛诱导的半胱天冬酶-9激活。这些发现表明，丙烯醛激活了Fas受体途径，该途径发生在线粒体途径的上游。尽管抑制了Fas受体途径，但半胱天冬酶-9仍被激活，这表明丙烯醛也可独立于受体途径触发线粒体途径。这些发现增进了我们对反应性醛类丙烯醛毒性机制的理解，其在多种疾病状态中具有广泛影响，这些疾病状态似乎是由氧化应激和脂质过氧化介导的。
