Abstract
BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.Methods and ResultsExperimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.ConclusionsRho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.
Highlights
Abdominal aortic aneurysm (AAA) is a substantial burden in the developed countries, due in part to aging of the society [1]
We examined whether 1) statins, calcium channel blockers, or their combination therapy suppress AAA formation in mice model, 2) Rho-kinase is involved in the mechanism of AAA inhibition by pharmacological therapy and 3) Rho-kinase is up-regulated in the human AAA
ElasticaMasson staining demonstrated that the elastic lamellae were severely destroyed in the angiotensin II (AngII) group compared with the sham group, which was significantly suppressed in the combination group, but not in each monotherapy group (Figure S2, A-K)
Summary
Abdominal aortic aneurysm (AAA) is a substantial burden in the developed countries, due in part to aging of the society [1]. Recent studies demonstrated that both 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and calcium channel blockers (CCBs) exert beneficial effects on cardiovascular disease [3,4,5]. It is, controversial whether statins suppress the development and progression of AAA [6,7,8]. Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rhokinase inhibition may be involved
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