Lin Yuan, Feng Mei, Lu Chang-Wu, Lei Yan-Ping, He Zhi-Min, Xiong Yan
Department of Pharmacology, Guangzhou Institute of Snake Venom Research, Guangzhou Medical University, Guangzhou 511436, Guangdong, PR China.
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, PR China.
Eur J Pharmacol. 2017 Mar 5;798:43-48. doi: 10.1016/j.ejphar.2017.01.041. Epub 2017 Feb 3.
Endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis. Endogenous inhibitor of nitric oxide synthase (NOS) asymmetric dimethylarginine (ADMA) has been recognized as an independent risk factor of endothelial dysfunction and the biomarker of atherosclerosis. This study was to investigate whether endogenous ADMA and its metabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) were involved in mechanisms of captopril protection against endothelial dysfunction in high fat diet feeding rabbits. Half of model rabbits were treated with captopril (10mg/kg/d, i.g.) for 12w. Vascular morphology and serum lipid profiles were detected. Serum ADMA concentration were assayed by high performance liquid chromatography. Recombinant DDAH2 gene adenoviruses were ex vivo transferred to thoracic aortas of high fat diet feeding rabbits. Endothelium-dependent relaxation of aortas response to acetylcholine and DDAH activity were measured. Atherosclerosis was confirmed in high fat diet feeding rabbits by increased serum lipid profiles and morphologic changes of vascular wall. Serum ADMA levels were significantly increased in hyperlipidemic rabbits accompanied with impairment of endothelium-dependent relaxation and inhibition of DDAH activity in thoracic aortas. Captopril treatment not only decreased vascular intima thickening and serum ADMA concentration but also preserved vascular DDAH activity and endothelium-dependent relaxation in hyperlipidemic rabbits without influence on serum lipid profiles. Similar beneficial effects on endothelial function and DDAH activity could be achieved by DDAH2 gene transfection. These results indicated that captopril could protect against injuries of vascular morphology and endothelial function in hyperlipidemic rabbits, the mechanisms may be related to the preservation of DDAH activity and decrease of ADMA accumulation in vascular endothelium.
内皮功能障碍在动脉粥样硬化的发病机制中起关键作用。一氧化氮合酶（NOS）的内源性抑制剂不对称二甲基精氨酸（ADMA）已被公认为内皮功能障碍的独立危险因素和动脉粥样硬化的生物标志物。本研究旨在探讨内源性ADMA及其代谢酶二甲基精氨酸二甲胺水解酶（DDAH）是否参与卡托普利对高脂饮食喂养兔内皮功能障碍的保护机制。将一半模型兔用卡托普利（10mg/kg/d，灌胃）治疗12周。检测血管形态和血脂谱。采用高效液相色谱法测定血清ADMA浓度。将重组DDAH2基因腺病毒体外转染至高脂饮食喂养兔的胸主动脉。测定主动脉对乙酰胆碱的内皮依赖性舒张反应和DDAH活性。高脂饮食喂养兔血清脂质水平升高和血管壁形态学改变证实了动脉粥样硬化的存在。高脂血症兔血清ADMA水平显著升高，同时伴有胸主动脉内皮依赖性舒张功能受损和DDAH活性抑制。卡托普利治疗不仅可减轻高脂血症兔血管内膜增厚和血清ADMA浓度，还可保留血管DDAH活性和内皮依赖性舒张功能，且对血脂谱无影响。DDAH2基因转染对内皮功能和DDAH活性也有类似的有益作用。这些结果表明，卡托普利可保护高脂血症兔的血管形态和内皮功能免受损伤，其机制可能与保留DDAH活性和减少血管内皮中ADMA蓄积有关。
