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Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice
Published on: September 28, 2015
Combination therapy with atorvastatin and amlodipine suppresses angiotensin II-induced aortic aneurysm formation
Kikuyo Takahashi1, Yasuharu Matsumoto, Zhulanqiqige Do e
1Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Background:
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. 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 Results:
Experimental 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.
Conclusions:
Rho-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.
Insights
Combination therapy of amlodipine and atorvastatin effectively inhibits abdominal aortic aneurysm (AAA) expansion in mice by targeting Rho-kinase. This combination therapy, unlike monotherapy, reduces AAA lesion severity and Rho-kinase activity.
Area of Science:
- Cardiovascular Research
- Vascular Biology
- Pharmacology
Background:
- Abdominal aortic aneurysm (AAA) is a critical vascular condition with controversial treatments.
- Calcium channel blockers (CCBs) may inhibit Rho-kinase, a key factor in cardiovascular diseases.
- The role of Rho-kinase in human AAA pathogenesis remains largely unexplored.
Purpose of the Study:
- To investigate the efficacy of combination therapy with atorvastatin and amlodipine in an experimental AAA model.
- To explore the association between Rho-kinase activity and AAA formation.
- To determine if Rho-kinase inhibition is involved in the therapeutic effect of the combination therapy.
Main Methods:
- An experimental AAA model was created in Apolipoprotein E-deficient mice using angiotensin II infusion.
- Mice were treated with saline, angiotensin II alone, atorvastatin, amlodipine, or a combination of atorvastatin and amlodipine.
- Aortic diameter, apoptosis, elastin degradation, and Rho-kinase activity were assessed. Immunohistochemistry was used on human AAA samples.
Main Results:
- Combination therapy significantly suppressed AAA expansion, apoptosis, and elastin degradation compared to sham and monotherapy groups.
- Rho-kinase activity and matrix metalloproteinase activity were elevated in AngII-induced AAA lesions and reduced by combination therapy.
- Rho-kinase was found to be up-regulated in human AAA lesions.
Conclusions:
- Rho-kinase is upregulated in human AAA, suggesting its involvement in AAA pathogenesis.
- Combination therapy with amlodipine and atorvastatin effectively suppresses AAA formation in mice.
- Rho-kinase inhibition is a potential mechanism underlying the therapeutic benefits of this combination therapy.
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