Wei Shu-jian, Xing Jun-hui, Wang Bai-lu, Xue Li, Wang Jia-li, Li Rui, Qin Wei-dong, Wang Juan, Wang Xu-ping, Zhang Ming-xiang, Chen Yu-guo
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, Qilu Hospital, Jinan, Shandong, China.
Biochim Biophys Acta. 2013 Mar;1833(3):479-86. doi: 10.1016/j.bbamcr.2012.11.007. Epub 2012 Nov 13.
Lipid peroxidation plays a critical role in cardiovascular diseases. Aldehydes are the major end products of lipid peroxidation and can be metabolized into less reactive chemical species by aldehyde dehydrogenase 2 (ALDH2). However, ALDH2 dehydrogenase activity can be affected by many factors including reactive oxygen species. To elucidate how reactive oxygen species inhibit ALDH2 dehydrogenase activity, we stimulated human aortic endothelial cells (HAECs) with oxidized low-density lipoproteins (ox-LDL) and performed a myocardial ischemia-reperfusion model. Ox-LDL treatment and ischemia-reperfusion injury inhibited ALDH2 dehydrogenase activity. Poly(ADP-ribose) polymerase (PARP) was activated by ox-LDL stimulation and ischemia-reperfusion injury and PARP inhibition partly restored ALDH2 dehydrogenase activity in ox-LDL treated HAECs and ischemia-reperfusion rat hearts. SIRT3 was upregulated by ox-LDL stimulation and ischemia-reperfusion injury and downregulated by PARP inhibition. Using siRNA to knock down SIRT3, we demonstrated that SIRT3 mediated deacetylation decreased ALDH2 dehydrogenase activity and PARP inhibition partly restored ALDH2 dehydrogenase activity through preventing SIRT3 expression and subsequently preserving ALDH2 acetylation.
脂质过氧化在心血管疾病中起关键作用。醛类是脂质过氧化的主要终产物，可被醛脱氢酶2（ALDH2）代谢为反应性较低的化学物质。然而，ALDH2脱氢酶活性会受到包括活性氧在内的多种因素影响。为阐明活性氧如何抑制ALDH2脱氢酶活性，我们用氧化型低密度脂蛋白（ox-LDL）刺激人主动脉内皮细胞（HAECs）并建立心肌缺血再灌注模型。ox-LDL处理和缺血再灌注损伤均抑制了ALDH2脱氢酶活性。poly（ADP-核糖）聚合酶（PARP）在ox-LDL刺激和缺血再灌注损伤下被激活，PARP抑制可部分恢复ox-LDL处理的HAECs及缺血再灌注大鼠心脏中的ALDH2脱氢酶活性。SIRT3在ox-LDL刺激和缺血再灌注损伤下上调，在PARP抑制下下调。利用小干扰RNA敲低SIRT3，我们证明SIRT3介导的去乙酰化降低了ALDH2脱氢酶活性，PARP抑制通过阻止SIRT3表达并随后维持ALDH2乙酰化而部分恢复了ALDH2脱氢酶活性。
