Han Xianlin, Yang Jingyue, Yang Kui, Zhao Zhongdan, Abendschein Dana R, Gross Richard W
Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Biochemistry. 2007 May 29;46(21):6417-28. doi: 10.1021/bi7004015. Epub 2007 May 8.
Recently, we have identified the dramatic depletion of cardiolipin (CL) in diabetic myocardium 6 weeks after streptozotocin (STZ) injection that was accompanied by increases in triacylglycerol content and multiple changes in polar lipid molecular species. However, after 6 weeks in the diabetic state, the predominant lipid hallmarks of diabetic cardiomyopathy were each present concomitantly, and thus, it was impossible to identify the temporal course of lipid alterations in diabetic myocardium. Using the newly developed enhanced shotgun lipidomics approach, we demonstrated the dramatic loss of abundant CL molecular species in STZ-treated hearts at the very earliest stages of diabetes accompanied by a profound remodeling of the remaining CL molecular species including a 16-fold increase in the content of 18:2-22:6-22:6-22:6 CL. These alterations in CL metabolism occur within days after the induction of the diabetic state and precede the triacylglycerol accumulation manifest in diabetic myocardium. Similarly, in ob/ob mice, a dramatic and progressive redistribution from 18:2 FA-containing CL molecular species to 22:6 FA-containing CL molecular species was also identified. Collectively, these results demonstrate alterations in CL hydrolysis and remodeling at the earliest stages of diabetes and are consistent with a role for alterations in CL content in precipitating mitochondrial dysfunction in diabetic cardiomyopathy.
最近，我们发现链脲佐菌素（STZ）注射6周后糖尿病心肌中心磷脂（CL）显著减少，同时甘油三酯含量增加，极性脂质分子种类发生多种变化。然而，在糖尿病状态持续6周后，糖尿病性心肌病的主要脂质特征同时出现，因此，无法确定糖尿病心肌中脂质变化的时间进程。使用新开发的增强型鸟枪法脂质组学方法，我们证明在糖尿病最早阶段，STZ处理的心脏中丰富的CL分子种类显著减少，同时剩余CL分子种类发生深刻重塑，包括18:2-22:6-22:6-22:6 CL含量增加16倍。这些CL代谢变化在糖尿病状态诱导后数天内发生，且早于糖尿病心肌中甘油三酯的积累。同样，在ob/ob小鼠中，也发现了从含18:2 FA的CL分子种类到含22:6 FA的CL分子种类的显著且渐进的重新分布。总体而言，这些结果表明糖尿病最早阶段CL水解和重塑发生改变，并且与CL含量改变在糖尿病性心肌病中引发线粒体功能障碍的作用一致。
