PD123319 Augments Angiotensin II-Induced Abdominal Aortic Aneurysms through an AT2 Receptor-Independent Mechanism

Background
AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs), although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.
Methods and Results
Male AT2 receptor wild type (AT2 +/y) and deficient (AT2 -/y) mice in an LDL receptor −/− background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min). AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day) and AngII were co-infused into male LDL receptor −/− mice that were either AT2 +/y or −/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.
Conclusions
AT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism.

研究背景
AT2受体（AT2 receptor）在腹主动脉瘤（abdominal aortic aneurysms, AAA）发生发展中的功能尚不明确，尽管采用AT2受体拮抗剂PD123319的药理学研究已提示其可能参与该病理过程。本研究旨在结合遗传学与药理学手段，明确AT2受体在血管紧张素II（Angiotensin II, AngII）诱导的腹主动脉瘤中的作用。此外，本研究还界定了AT2受体在AngII诱导的动脉粥样硬化与胸主动脉瘤中的效应。

方法与结果
将处于低密度脂蛋白受体（LDL receptor）−/− 遗传背景下的雄性AT2受体野生型（AT2 +/y）与敲除型（AT2 -/y）小鼠饲喂富含饱和脂肪的饲料，并分别输注生理盐水或AngII（500 ng/kg/min）。AngII输注期间，AT2受体敲除对小鼠收缩压无显著影响。尽管AngII输注可诱导腹主动脉瘤形成，但AT2受体敲除既未显著影响肾上主动脉的最大直径，也未显著改变腹主动脉瘤的发生率。
将AT2受体拮抗剂PD123319（3 mg/kg/天）与AngII联合输注给AT2基因型为+/y或-/y的雄性低密度脂蛋白受体敲除小鼠。结果显示，PD123319对野生型或AT2受体敲除小鼠的收缩压均无显著影响。与本团队此前的研究结果一致，PD123319可增强AngII诱导的腹主动脉瘤形成，但该效应的发生与AT2受体基因型无关。无论是AT2受体敲除还是PD123319处理，均未对AngII诱导的胸主动脉瘤或动脉粥样硬化产生显著影响。

研究结论
AT2受体敲除不会影响AngII诱导的腹主动脉瘤、胸主动脉瘤及动脉粥样硬化的发生发展。PD123319可通过不依赖AT2受体的机制增强AngII诱导的腹主动脉瘤形成。