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.
- Received March 15, 2015.
- Revision received March 30, 2015.
- Accepted July 1, 2015.
- © 2015 American Heart Association, Inc.