Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats
Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats
复制标题
DOI：
10.1016/j.taap.2016.04.006
复制
发表时间：
2016-06-15
影响因子：
3.8
通讯作者：
Skrzydlewska, Elzbieta
中科院分区：
文献类型：
--
作者：
Biernacki, Michal;Luczaj, Wojciech;Skrzydlewska, Elzbieta
高血压伴随着内源性大麻素和抗氧化系统的紊乱。因此，高血压的潜在药物治疗应该被视为这两个代谢系统的调节器。本研究旨在观察长期给予脂肪酸酰胺水解酶抑制剂[3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate(URB597)对高血压大鼠肝脏氧化还原平衡和内源性大麻素系统的影响。高血压引起内源性大麻素[花生胺(AEA)、2-花生四烯酰基甘油(2-AG)和N-花生四烯酰基多巴胺(NADA)]和CB1受体水平升高，FAAH和单酰甘油脂肪酶(MAGL)活性升高。这些效应伴随着活性氧水平的升高、抗氧化剂活性/水平的降低、转录因子Nrf2表达的增强以及Nrf2激活剂和抑制物的改变。此外，还观察到脂质、DNA和蛋白质氧化修饰的显著增加，这导致促凋亡半胱氨酸酶水平的提高。给高血压大鼠灌胃URB597后，AEA、NADA和CB1受体水平进一步升高，维生素E和维生素C水平、谷胱甘肽过氧化物酶和谷胱甘肽还原酶活性及Nrf2表达降低。因此，在给予URB597后，细胞成分的氧化修饰增加，而炎症反应减少。这项研究表明，用URB597慢性治疗高血压大鼠会扰乱内源性大麻系统，从而导致氧化还原状态的失衡。这种失衡增加了亲电性脂质过氧化产物的水平，这些产物后来参与了肝脏动态平衡的代谢紊乱。(C)2016 Elsevier Inc.保留所有权利。
Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. (C) 2016 Elsevier Inc. All rights reserved.