Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation

Angiotensin IV (Ang IV), as an effector peptide of the rennin-angiotensin system, possesses many biological properties yet not completely known. In this study, we aimed to investigate the role of Ang IV in the development of Ang II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II infusion to induce AAA, and animals were treated with Ang II (1.44 mg/kg per day) plus no treatment, Ang II (1.44 mg/kg per day) plus low-, medium-, and high-dose Ang IV (0.72, 1.44, and 2.88 mg/kg per day, respectively). The incidence of AAA was 87.5%, 66.7%, 37.5%, and 83.3% in the no treatment, the low-, medium-, or high-dose Ang IV group, respectively. Compared with the no treatment group, medium-dose Ang IV treatment markedly reduced macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein 1, interleukin 6, and intercellular adhesion molecule 1; the expression and activity of metalloproteinases 2 and 9; but increased smooth muscle cells, and collagen content in AAA. However, high-dose Ang IV treatment did not have obvious protective effect. The beneficial effect of medium-dose Ang IV may be contributed to the stimulation of type 4 angiotensin receptor (AT4R) and AT2R with suppression of AT1R, activation of Akt, and inhibition of nuclear factor-κB, as these beneficial effects were largely reversed by cotreatment with the AT4R antagonist divalinal-Ang IV in Ang II-infused mice or with the Akt inhibitor A6730 in Ang II-stimulated human smooth muscle cells. Therefore, medium dose of Ang IV may provide a novel and promising approach to the treatment of AAA.