Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway

Abstract

Aims: Abdominal aortic aneurysm (AAA) is a life-threatening disease affecting almost 10% of the population over the age of 65. Nitrogen-containing bisphosphonates (N-BPs) have been shown to exert anti-atherogenic and anti-angiogenic effects, but the potential effects of N-BPs on AAA remain unclear. Here, we tested whether a potent N-BP, zoledronate, can attenuate the formation of Angiotensin II (Ang II)-induced AAA in hyperlipidaemic mice. Methods and results: Low-density lipoprotein receptor-/- (LDLR -/-) mice infused for 28 days with Ang II were treated with placebo and 100 μg/kg/day zoledronate. Continuous Ang II infusion in LDLR -/- mice exhibited a 59% incidence of AAA formation, and treatment with zoledronate decreased AAA formation (21%). Compared with the saline group, administration of zoledronate in Ang II-infused LDLR-/- mice attenuated the expansion of the suprarenal aorta (maximal aortic diameter), reduced elastin degradation in the media layer of the aorta, and significantly diminished vascular inflammation by reduction in vascular cell adhesion molecule expression and macrophage accumulation. Treatment with zoledronate decreased matrix metalloproteinase-2 (MMP-2) in aortic tissues. Zoledronate-treated mice had significant down-regu-lation of JNK, NF-κB, and reduced Ang II-induced Rho/ROCK activation. Zoledronate reduced monocytes adherence to human aortic endothelial cells in vitro. Conclusion: Zoledronate-attenuated Ang II induced AAA formation by suppression of MMP-2 activity and suppressed vascular inflam-mation and Ang II-induced Rho/ROCK activities. © The Author 2013.