Improvement of aortic valve stenosis by ApoA‐I mimetic therapy is associated with decreased aortic root and valve remodelling in mice

Background and Purpose

We have shown that infusions of apolipoprotein A‐I (ApoA‐I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA‐I mimetic therapy in mice with calcific or fibrotic AVS.

Experimental Approach

Apolipoprotein E‐deficient (ApoE^−/−) mice and mice with Werner progeria gene deletion (Wrn^Δhel/Δhel) received high‐fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA‐I mimetic peptide infusions (ApoA‐I treated groups, 100 mg·kg⁻¹ for ApoE^−/− mice; 50 mg·kg⁻¹ for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology.

Key Results

Aortic valve area (AVA) increased in both ApoE^−/− and Wrn mice treated with the ApoA‐I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA‐I treated ApoE^−/− mice. The type I/III collagen ratio was lower in the sinus wall of ApoA‐I treated ApoE^−/− mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA‐I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA.

Conclusions and Implications

ApoA‐I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice.

DOI: 10.1111/bph.12236

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