Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits
Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits
复制标题
保持血管 DDAH 活性有助于卡托普利保护高脂血症兔免受内皮功能障碍
DOI：
10.1016/j.ejphar.2017.01.041
复制
发表时间：
2017-03-05
影响因子：
5
通讯作者：
Xiong, Yan
中科院分区：
文献类型：
--
作者：
Lin, Yuan;Feng, Mei;Xiong, Yan
内皮功能障碍在动脉粥样硬化的发病机制中起着关键作用。内源性一氧化氮合酶（NOS）抑制剂不对称二甲基精氨酸（ADMA）已被认为是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氨基水解酶（DDAH）是否参与了巯甲丙脯酸（Captopril）对高脂喂养兔血管内皮功能障碍的保护机制。模型组用巯甲丙脯酸10 mg/kg/d，i.g. 12W。检测血管形态学和血脂谱。高效液相色谱法测定血清ADMA浓度。将重组DDAH 2基因腺病毒体外转染高脂饲料喂养的家兔胸主动脉。血管内皮依赖性舒张反应的乙酰胆碱和DDAH活性进行了测定。高脂饲料喂养的家兔血脂水平升高和血管壁形态学改变证实了动脉粥样硬化。高脂血症家兔血清ADMA水平显著升高，并伴有胸主动脉内皮依赖性舒张功能受损和DDAH活性抑制。卡托普利治疗不仅降低血管内膜增厚和血清ADMA浓度，但也保持血管DDAH活性和内皮依赖性舒张在高血压兔血脂谱没有影响。DDAH 2基因转染对内皮功能和DDAH活性也有类似的有益作用。提示：卡托普利对高血压兔血管形态和内皮功能的损伤具有保护作用，其机制可能与维持血管内皮DDAH活性和减少血管内皮ADMA蓄积有关。
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 (10 mg/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.