Abstract 11426: Combination Therapy with Amlodipine and Atrovastatin Prevents Abdominal Aortic Aneurysm Formation in ApoE-Deficient Mice

Abstract

Background: Recent studies have revealed that both calcium channel blockers (CCBs) and statins exert beneficial effect on various cardiovascular diseases. However, it remains unknown whether CCBs, statins, and their combination therapy prevent formation of abdominal aortic aneurysm (AAA), which is an emerging problem in the aging society. In this study, we thus addressed this important issue in mice.

Methods and Results: Six-month-old apolipoprotein E-deficient (ApoE-/-) mice were infused with angiotensin II (AngII, 2500 ng/kg/min) for 1 month (n=64). They were randomly divided into the following 5 groups; group 1 with saline infusion alone (sham); group 2, AngII infusion alone (AngII); group 3 AngII infusion plus amlodipine (1 mg/kg/day, AM); group 4, AngII infusion plus atorvastatin (10 mg/kg/day, AT); and group 5, AngII infusion plus combination therapy with amlodipine (1 mg/kg/day) and atorvastatin (10 mg/kg/day) (Com). There was no difference in blood pressure among the 4 AngII-infusion groups. The combination therapy significantly inhibited AngII-induced increase in maximal aortic diameter and the ratio (%) of advanced type III and IV morphology at the AAA lesion, whereas monotherapies had no inhibitory effects [sham, 1.03±0.05 (0%); AngII, 2.01±0.82 (33%); AM, 1.71±0.78 (33%); AT, 2.11±0.98 (33%); Com, 1.10±0.10 mm (0%); P<0.05, AngII vs. Com]. The combination therapy, but not each monotherapy, inhibited AngII-induced decrease in the endothelial KLF2 expression (a marker of shear stress) at the AAA lesion. In addition, the combination therapy markedly reduced AngII-induced inflammatory cells recruitment, apoptosis and elastin degradation at the AAA lesion, while monotherapies had no inhibitory effects. Moreover, immunoreactivities for Rho-kinase expression and activity were increased in the AngII-induced AAA lesion as compared to sham, which was markedly inhibited by the combination therapy but not by each monotherapy.

Conclusions: This study demonstrates for the first time that the combination therapy with amlodipine and atorvastatin, but not each monotherapy, prevents AAA formation in mice, for which inhibition of Rho-kinase activation associated with low shear stress, inflammation and apoptosis may be involved.