The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis
The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis
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DOI：
10.1007/s00125-016-3977-5
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发表时间：
2016-08-01
期刊：
影响因子：
8.2
通讯作者：
Allen, Terri J.
中科院分区：
文献类型：
--
作者：
Chow, Bryna S. M.;Koulis, Christine;Allen, Terri J.
目的/假设血管紧张素II被认为是通过其血管紧张素II 1型受体（AT(1)R）亚型信号传导驱动糖尿病相关动脉粥样硬化病理事件的关键介质。然而，其通过血管紧张素II 2型受体（AT(2)R）亚型的作用仍然知之甚少。这项研究首次探讨了新型选择性AT(2)R激动剂化合物21 （C21）在糖尿病相关动脉粥样硬化（DAA）实验模型中的作用。方法以链脲佐菌素诱导的糖尿病apoe基因敲除小鼠为研究对象，分别用载药（0.1 mol/l柠檬酸缓冲液）、C21 （1 mg/kg / d）、坎地沙坦西列地酯（4 mg/kg / d）或C21 +坎地沙坦西列地酯治疗20周。用C21处理的人主动脉内皮细胞和单核细胞培养物建立体外DAA模型。实验结束时，评估斑块含量和氧化应激、炎症和纤维化标志物。结果C21治疗可显著减轻DAA小鼠体内主动脉斑块沉积，并可减少巨噬细胞和炎症、氧化应激和纤维化介质的浸润。另一方面，与单独治疗相比，C21和坎地沙坦（AT(1)R拮抗剂）联合治疗在减轻DAA病理方面似乎具有有限的附加效应。同样，在体外水平，C21被发现具有深远的抗动脉粥样硬化作用，特别是在高血糖的情况下。引人注目的是，C21的这些动脉粥样硬化保护作用被AT(2)R拮抗剂PD123319完全阻断。综上所述，这些发现为C21作为单药治疗DAA提供了新的机制和潜在的治疗见解。
Aims/hypothesis Angiotensin II is well-recognised to be a key mediator in driving the pathological events of diabetes-associated atherosclerosis via signalling through its angiotensin II type 1 receptor (AT(1)R) subtype. However, its actions via the angiotensin II type 2 receptor (AT(2)R) subtype are still poorly understood. This study is the first to investigate the role of the novel selective AT(2)R agonist, Compound 21 (C21) in an experimental model of diabetes-associated atherosclerosis (DAA).Methods Streptozotocin-induced diabetic Apoe-knockout mice were treated with vehicle (0.1 mol/l citrate buffer), C21 (1 mg/kg per day), candesartan cilexetil (4 mg/kg per day) or C21 + candesartan cilexetil over a 20 week period. In vitro models of DAA using human aortic endothelial cells and monocyte cultures treated with C21 were also performed. At the end of the experiments, assessment of plaque content and markers of oxidative stress, inflammation and fibrosis were conducted.Results C21 treatment significantly attenuated aortic plaque deposition in a mouse model of DAA in vivo, in association with a decreased infiltration of macrophages and mediators of inflammation, oxidative stress and fibrosis. On the other hand, combination therapy with C21 and candesartan (AT(1)R antagonist) appeared to have a limited additive effect in attenuating the pathology of DAA when compared with either treatment alone. Similarly, C21 was found to confer profound anti-atherosclerotic actions at the in vitro level, particularly in the setting of hyperglycaemia. Strikingly, these atheroprotective actions of C21 were completely blocked by the AT(2)R antagonist PD123319.Conclusions/interpretation Taken together, these findings provide novel mechanistic and potential therapeutic insights into C21 as a monotherapy agent against DAA.