抑制可溶性环氧化物水解酶可限制线粒体损伤并在缺血性损伤后保留功能。
Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury.
作者信息
Akhnokh Maria K, Yang Feng Hua, Samokhvalov Victor, Jamieson Kristi L, Cho Woo Jung, Wagg Cory, Takawale Abhijit, Wang Xiuhua, Lopaschuk Gary D, Hammock Bruce D, Kassiri Zamaneh, Seubert John M
机构信息
Faculty of Pharmacy and Pharmaceutical Sciences, 2-020M Katz Group Centre for Pharmacy and Health Research, University of Alberta Edmonton, AB, Canada.
Guangdong Laboratory Animal Monitoring Institute Guangdong, China.
出版信息
Front Pharmacol. 2016 Jun 7;7:133. doi: 10.3389/fphar.2016.00133. eCollection 2016.
AIMS
Myocardial ischemia can result in marked mitochondrial damage leading to cardiac dysfunction, as such identifying novel mechanisms to limit mitochondrial injury is important. This study investigated the hypothesis that inhibiting soluble epoxide hydrolase (sEH), responsible for converting epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids protects mitochondrial from injury caused by myocardial infarction.
METHODS
sEH null and WT littermate mice were subjected to surgical occlusion of the left anterior descending (LAD) artery or sham operation. A parallel group of WT mice received an sEH inhibitor, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; 10 mg/L) or vehicle in the drinking water 4 days prior and 7 days post-MI. Cardiac function was assessed by echocardiography prior- and 7-days post-surgery. Heart tissues were dissected into infarct, peri-, and non-infarct regions to assess ultrastructure by electron microscopy. Complexes I, II, IV, citrate synthase, PI3K activities, and mitochondrial respiration were assessed in non-infarct regions. Isolated working hearts were used to measure the rates of glucose and palmitate oxidation.
RESULTS
Echocardiography revealed that tAUCB treatment or sEH deficiency significantly improved systolic and diastolic function post-MI compared to controls. Reduced infarct expansion and less adverse cardiac remodeling were observed in tAUCB-treated and sEH null groups. EM data demonstrated mitochondrial ultrastructure damage occurred in infarct and peri-infarct regions but not in non-infarct regions. Inhibition of sEH resulted in significant improvements in mitochondrial respiration, ATP content, mitochondrial enzymatic activities and restored insulin sensitivity and PI3K activity.
CONCLUSION
Inhibition or genetic deletion of sEH protects against long-term ischemia by preserving cardiac function and maintaining mitochondrial efficiency.
目的
心肌缺血可导致明显的线粒体损伤，进而引起心脏功能障碍，因此确定限制线粒体损伤的新机制具有重要意义。本研究探讨了以下假说：抑制负责将环氧二十碳三烯酸转化为二羟基二十碳三烯酸的可溶性环氧化物水解酶（sEH）可保护线粒体免受心肌梗死所致的损伤。
方法
将sEH基因敲除小鼠和野生型同窝小鼠进行左前降支（LAD）动脉手术结扎或假手术。另一组野生型小鼠在心肌梗死前4天和后7天，通过饮用水给予sEH抑制剂反式-4-[4-(3-金刚烷-1-基脲基)-环己氧基]-苯甲酸（tAUCB；10 mg/L）或溶剂对照。在手术前和术后7天通过超声心动图评估心脏功能。将心脏组织分为梗死区、周边区和非梗死区，通过电子显微镜评估超微结构。在非梗死区评估复合物I、II、IV、柠檬酸合酶、PI3K活性和线粒体呼吸。使用离体工作心脏测量葡萄糖和棕榈酸氧化率。
结果
超声心动图显示，与对照组相比，tAUCB治疗或sEH缺乏可显著改善心肌梗死后的收缩和舒张功能。在tAUCB治疗组和sEH基因敲除组中观察到梗死面积扩大减少和不良心脏重塑减轻。电子显微镜数据表明，线粒体超微结构损伤发生在梗死区和梗死周边区，但非梗死区未发生。抑制sEH可显著改善线粒体呼吸、ATP含量、线粒体酶活性，并恢复胰岛素敏感性和PI3K活性。
结论
抑制或基因缺失sEH可通过保护心脏功能和维持线粒体效率来预防长期缺血。
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