PS-BPB01-3: ANGIOTENSIN (1–7)-MEDIATED PREVENTIVE EFFECT OF ANGIOTENSIN II TYPE 1 RECEPTOR ANTAGONISTS ON ABDOMINAL AORTIC ANEURYSM PROGRESSION IN OPG-KO MICE

Abstract

Objective: Hypertension is one of the major risk factors for onset of abdominal aortic aneurysm (AAA), which is a local enlargement of the abdominal aorta. Therefore, anti-hypertensive drugs, including angiotensin (Ang) II type 1 receptor blocker (ARB), have been expected to limit AAA growth. However, the efficacy of ARB against AAA in clinical settings is controversial. In the present study, we attempted to elucidate a mechanism by which ARB inhibits AAA progression. Design and method: To examine the effect of ARB against AAA progression, olmesartan (20 mg/kg/day) was administered orally to male wild-type mice and osteoprotegerin (Opg)-knockout (KO) mice, from two weeks before the AAA induction by using a CaCl2 application on the abdominal aortae to the sacrifice date. Since Opg could bind to tumor necrosis factor-related apoptosis-inducing ligand (Trail) for inhibiting its activity, deficiency of the Opg gene has been reported to induce overactivation of the Trail induced-c-Jun N-terminal kinase (Jnk)/matrix metalloproteinase 9 (Mmp9) pathway in CaCl2-induced mouse AAA model, resulting in serious AAA progression. Here, we tested whether olmesartan could prevent AAA progression associated with Trail/Jnk/Mmp9 pathway. Results: We found that olmesartan prevented excessive aortic enlargement and serious degenerative change of the aortic tissue in Opg-KO mice at six weeks after AAA induction, but not affected AAA formation in wild-type mice. In Opg-KO mice, olmesartan reduced co-localized expression of phosphorylated Jnk and Mmp9 in the tunica media. Then, we tested whether Ang (1–7), the blood level of which is increased by ARB administration, is associated with the preventive effect of olmesartan, because Ang (1–7) had been reported to reduce the Jnk phosphorylation. Consistent with previous studies, olmesartan increased serum level of Ang (1–7) in our AAA model. In vascular smooth muscle cells, Ang (1–7) inhibited the phosphorylation of Jnk and the increase of downstream Mmp9 mRNA expression induced by Trail. Furthermore, administration of an Ang (1–7) antagonist, A779, to Opg-KO mice diminished the preventive effect of ARB against the AAA progression. Notably, olmesartan slightly lowered blood pressure in Opg-KO mice, while A779 did not affect the blood pressure-lowering effect of olmesartan. Conclusions: Our results indicate that ARB prevents the AAA progression in Opg-KO mice via the inhibition of Trail-induced Jnk-Mmp9 pathway. Furthermore, it is suggested that the increase of Ang (1–7) may play a key role in the preventive effect of ARB on the AAA progression.