LAUSR

Objective: We studied the effects of selective AT2 receptor agonist, compound 21, (C21) treatment on experimental abdominal aortic aneurysm (AAA) formation in rats. Design and method: AAA was induced by perfusion of isolated aortic segments with elastase in normotensive Wistar rats. Treatment with C21 (0.03 mg/kg daily) was started after operation and continued for 14 days. Sham operated animals and vehicle-treated animals after aneurysm induction (AI) served as controls. Aortic diameter and blood velocities were measured infrarenally before and on days 7 and 14 post operation via ultrasound biomicroscopy. Analysis of pulse propagation velocity (PPV) and distensibility was performed using the Vevo Vasc® software. Hemodynamic parameters were measured via tail cuff and intraventricular Samba catheter. Aortic tissue expressions of MMP9, IL6, IL1beta, NFkappaB and MLKL as well as serum cytokines were analysed. Results: On day 14 post AI, infrarenal aortic diameter of AAA group was increased 1,55-fold compared to sham operated animals (2.65 mm ± 0.05, n = 8 vs. 1.7 mm ± 0.068, n = 6; p < 0.0001). C21 significantly decreased aortic diameter by 20% on day 7 post AI and by 28% on day 14 compared to vehicle-treated animals (1.9 mm ± 0.06, vs. 2.65 mm ± 0.06; p < 0.0001). Left ventricle parameters and blood pressure were not influenced by AI nor by additional treatment with C21. AI significantly reduced infrarenal blood velocity, distensibility and increased PPV. All these pathological effects were significantly ameliorated in C21 treated rats (p < 0, 0001; p < 0, 0001; p = 0, 0205; 2-wayANOVA). Treatment with C21 also reduced the expression of inflammatory markers IL1 beta, NF kappa B, protease MMP9 and MLKL, the marker of necroptotic cell death in the aortic media. Moreover, C21 reduced the increase of TGF-beta1 in serum (p = 0, 0055). Conclusions: The angiotensin AT2 receptor agonist, C21, prevents abdominal aortic aneurysm progression in the rat without affecting blood pressure or left ventricle parameters. C21 also prevents the decline of infrarenal aortic blood velocity, reduces the decrease of aortic wall distensibility at aneurysm site and the AAA-induced increase of inflammatory and necroptotic markers.