AT(2)R (Angiotensin AT2 Receptor) Agonist, Compound 21, Prevents Abdominal Aortic Aneurysm Progression in the Rat

The effects of the selective AT(2)R (angiotensin AT2 receptor) agonist, Compound 21 (C21), on abdominal aortic aneurysm formation were investigated in normotensive Wistar rats. Abdominal aortic aneurysm was induced by perfusion of isolated aortic segments with elastase. 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 served as controls. Aortic diameter, aortic wall distensibility, and pulse propagation velocity were measured via ultrasound. Hemodynamic parameters, aortic tissue protein expression, and serum cytokines were analyzed. On day 14 post aneurysm induction, aortic diameter of vehicle-treated animals was increased 1.6-fold compared with sham-operated rats (2.65 +/- 0.05 versus 1.70 +/- 0.06 mm; P<0.0001). C21 decreased aortic diameter in comparison to vehicle (1.9 +/- 0.06 versus 2.65 +/- 0.05; P<0.0001). Infrarenal blood velocity and aortic distensibility were reduced, whereas aortic wall stiffness was increased post aneurysm induction. These alterations were significantly ameliorated by treatment with C21 while blood pressure and cardiac contractility remained unchanged. Protein expression of IL-1 beta (interleukin-1 beta), NF kappa B (nuclear factor kappa B), MMP9 (matrix metalloproteinase 9), TGF-beta 1 (transforming growth factor-beta 1), and MLKL (mixed lineage kinase domain-like) in the aorta was significantly (P<0.05) down-regulated in the C21 group compared with vehicle. Serum concentration of TGF-beta 1 was decreased by C21 in comparison to vehicle (P<0.01). AT(2)R stimulation with C21 prevented extracellular matrix degradation, maintained vascular integrity of the aorta and prevented abdominal aortic aneurysm progression.