The effects of the selective, non-peptide angiotensin II Type 2 receptor agonist, compound 21 (C21), on abdominal aortic aneurysm (AAA) formation were investigated in male, normotensive Wistar rats.
AAA was induced by perfusion of isolated aortic segments with elastase (Anidjar/Dobrin model). Treatment with C21 (0.03mg/kg i.p. 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 diameters, pulse propagation velocity and wall distensibility, as well as blood velocities were measured at four abdominal aortic landmarks before aneurysm induction and on days 7 and 14 after operation via ultrasound biomicroscopy. Hemodynamic parameters were measured via the tail cuff method and intracardiac Samba catheter at day 14. Additionally, the effect of C21 on aortic expression of MMP-9, TIMP-1, IL-1 beta, NF-kappa B, CD68 and MLKL was studied via immunohistochemistry and western blot analysis. Serum analysis of cytokines IL-6, MCP-1 and TGF-beta was performed.
On day 14 post AI, infrarenal aortic diameter of vehicle-treated animals was increased 1,6-fold compared to sham operated rats (2.65 ± 0.05 mm vs. 1.70 ± 0.06 mm; p<0.0001). C21 significantly decreased aortic diameter by 20 % on day 7 post AI and by 28 % on day 14 as compared to vehicle-treated animals (1.9 mm ± 0.06 vs. 2.65 mm ± 0.05; p<0.0001). Infrarenal blood velocity and aortic distensibility were reduced, whereas aortic wall stiffness was increased post AI. These alterations were significantly ameliorated by treatment with C21 (p<0.0001; p<0.05). Blood pressure and cardiac contractility were not altered. Protein expression of IL-1 beta, NF-kappa B, MMP-9, TGF-beta1 and MLKL in the aorta was significantly (p<0.05) down-regulated in the C21 group compared with vehicle. In primary rat vascular smooth muscle cells, the release of MMP-9, TGF-beta1 and MLKL was significantly diminished after C21 (1µM) treatment. Serum concentration of TGF-beta1 was also decreased by C21 in comparison to vehicle (p<0.01).
AT2 receptor stimulation with C21 prevented extracellular matrix degradation, maintained vascular integrity of the aorta and prevented AAA progression.
Lange C, Sommerfeld M, Namsolleck P, Kintscher U, Unger T, Kaschina E
AT2R (Angiotensin AT2 Receptor) Agonist, Compound 21, Prevents Abdominal Aortic Aneurysm Progression in the Rat. Hypertension. 2018 Jul 9. pii: HYPERTENSIONAHA.118.11168. doi: 10.1161/HYPERTENSIONAHA.118.11168. [Epub ahead of print]
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