Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
Hum Gene Ther. 2020 Jun;31(11-12):639-650. doi: 10.1089/hum.2019.124. Epub 2020 Mar 4.
The pro-renin receptor (PRR) is an important novel component of the renin-angiotensin (Ang) system that has multiple functions, which are not yet completely understood. In this study, we aimed to explore the effect of PRR on the formation of Ang II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II (1.44 mg/kg/day) infusion to induce AAA followed by a treatment of saline, telmisartan, no treatment, Ad-EGFP, Ad-PRR, or Ad-PRR plus telmisartan. The incidence of AAA was 35%, 60%, 65%, 90%, and 55% in the Telmisartan, Vehicle, Ad-EGFP, Ad-PRR, and Ad-PRR+Telmisartan groups, respectively. Compared with the Vehicle and Ad-EGFP groups, PRR overexpression markedly increased macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α); the expression and activity of MMP2 and MMP9; NOX2 and NOX4 protein and mRNA expression; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity; extracellular-signal-regulated kinase (ERK) and P38MAPK expression; but decreased smooth muscle cells content in AAA. However, telmisartan reversed the adverse effects of PRR. In addition, ERK inhibitor PD98059 eliminated the acceleration of Ang II-induced AAA formation by PRR, and coadministration of telmisartan and PD98059 further abolished the adverse effects of PRR on Ang II-induced AAA formation. Thus, PRR plays an important role in the pathological development of AAA via both Ang II-dependent and Ang II-independent activation of ERK pathways. These results suggest that inhibition of PRR activation may be a promising approach to the treatment of AAA.
肾素受体（PRR）是肾素-血管紧张素（Ang）系统的一个重要新组成部分，具有多种尚未完全了解的功能。在这项研究中，我们旨在探讨 PRR 对载脂蛋白 E 敲除小鼠 Ang II 诱导的腹主动脉瘤（AAA）形成的影响。我们使用 Ang II（1.44mg/kg/天）输注诱导 AAA，随后给予生理盐水、替米沙坦、无治疗、Ad-EGFP、Ad-PRR 或 Ad-PRR+替米沙坦治疗。在替米沙坦、载体、Ad-EGFP、Ad-PRR 和 Ad-PRR+替米沙坦组中，AAA 的发生率分别为 35%、60%、65%、90%和 55%。与载体和 Ad-EGFP 组相比，PRR 过表达明显增加了巨噬细胞浸润；促炎细胞因子（包括单核细胞趋化蛋白-1（MCP-1）和肿瘤坏死因子-α（TNF-α））水平；MMP2 和 MMP9 的表达和活性；NOX2 和 NOX4 蛋白和 mRNA 表达；烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性；细胞外信号调节激酶（ERK）和 P38MAPK 表达；但 AAA 中的平滑肌细胞含量减少。然而，替米沙坦逆转了 PRR 的不良影响。此外，ERK 抑制剂 PD98059 消除了 PRR 对 Ang II 诱导的 AAA 形成的加速作用，替米沙坦和 PD98059 的联合给药进一步消除了 PRR 对 Ang II 诱导的 AAA 形成的不良影响。因此，PRR 通过激活 ERK 通路的 Ang II 依赖性和非依赖性途径，在 AAA 的病理发展中发挥重要作用。这些结果表明，抑制 PRR 激活可能是治疗 AAA 的一种有前途的方法。
