Roy Julie, Pallepati Pragathi, Bettaieb Ahmed, Tanel André, Averill-Bates Diana A
Département des sciences biologiques, TOXEN, Université du Québec à Montréal, Succursale Centre Ville, Canada.
Chem Biol Interact. 2009 Oct 7;181(2):154-67. doi: 10.1016/j.cbi.2009.07.001. Epub 2009 Jul 9.
Acrolein is a highly reactive, alpha,beta-unsaturated aldehyde that is an omnipresent environmental pollutant. Humans are exposed to acrolein in food, vapors of overheated cooking oil, cigarette smoke and by combustion of organic products. Acrolein is a toxic by-product of lipid peroxidation resulting from oxidative stress, which is implicated in pulmonary, cardiac and neurodegenerative diseases. Low dose exposure to toxic compounds often leads to adaptive responses. If the adaptive response does not counteract the adverse exposure, death processes such as apoptosis will eliminate the cell. This study investigates the activation of antiapoptosis survival factors in relation to the induction of cell death by apoptosis, following exposure to low doses of acrolein, in A549 human lung cells. Exposure to acrolein (<15microM, 30min) activated the survival factor AKT, which led to phosphorylation of Bad and induction of antiapoptosis proteins cIAP1/2. Acrolein (10-50microM, 30-60min) increased reactive oxygen species and caused mitochondrial membrane hyperpolarisation. Inhibition by the antioxidants catalase, polyethylene glycol-catalase, sodium pyruvate and MnTBAP showed that acrolein-induced reactive oxygen species were responsible for mitochondrial membrane hyperpolarisation. Acrolein (3-27microM, 30-60min) activated early stage processes in the mitochondrial pathway of apoptosis, such as Bax translocation to mitochondria, cytochrome c release, caspase-9 activation, and translocation of apoptosis-inducing factor to the nucleus. Acrolein (10-50microM) triggered later stage processes such as activation of caspases-3, -7 and -6, phosphatidylserine externalization and cleavage of poly(ADP)ribose polymerase after longer times (2h). These events were inhibited by polyethylene glycol-catalase, showing that apoptosis was mediated by overproduction of reactive oxygen species by acrolein. The novel findings show that antiapoptosis processes dominate at low dose (<15microM)/shorter exposure times to acrolein, whereas proapoptotic processes dominate at higher dose (10-50microM)/longer exposure times. Acrolein induced apoptosis through the mitochondrial pathway that was mediated by reactive oxygen species.
丙烯醛是一种高反应性的α,β-不饱和醛，是一种普遍存在的环境污染物。人类通过食物、过热食用油的蒸汽、香烟烟雾以及有机产品的燃烧接触到丙烯醛。丙烯醛是氧化应激导致的脂质过氧化的有毒副产物，与肺部、心脏和神经退行性疾病有关。低剂量接触有毒化合物通常会导致适应性反应。如果适应性反应不能抵消不良暴露，诸如凋亡等死亡过程将消除细胞。本研究调查了在A549人肺细胞中，低剂量丙烯醛暴露后，抗凋亡存活因子的激活与凋亡诱导的细胞死亡之间的关系。暴露于丙烯醛（<15微摩尔，30分钟）会激活存活因子AKT，这导致Bad磷酸化并诱导抗凋亡蛋白cIAP1/2。丙烯醛（10 - 50微摩尔，30 - 60分钟）会增加活性氧并导致线粒体膜超极化。抗氧化剂过氧化氢酶、聚乙二醇 - 过氧化氢酶、丙酮酸钠和MnTBAP的抑制作用表明，丙烯醛诱导的活性氧是线粒体膜超极化的原因。丙烯醛（3 - 27微摩尔，30 - 60分钟）激活凋亡线粒体途径的早期过程，如Bax转位至线粒体、细胞色素c释放、半胱天冬酶 - 9激活以及凋亡诱导因子转位至细胞核。丙烯醛（10 - 5微摩尔）在更长时间（2小时）后触发后期过程，如半胱天冬酶 - 3、 - 7和 - 6的激活、磷脂酰丝氨酸外翻以及聚（ADP）核糖聚合酶的裂解。这些事件被聚乙二醇 - 过氧化氢酶抑制，表明凋亡是由丙烯醛过量产生的活性氧介导的。新发现表明，在低剂量（<15微摩尔）/较短暴露时间下，抗凋亡过程在丙烯醛暴露中占主导，而在高剂量（10 - 50微摩尔）/较长暴露时间下，促凋亡过程占主导。丙烯醛通过由活性氧介导的线粒体途径诱导凋亡。
