ACE inhibition attenuates uremia-induced aortic valve thickening in a novel mouse model

Mikko A Simolin,Mikko I Mäyränpää,Satu Helske,Lars B Nielsen,Tanja X Pedersen,Susanne Bro,Petri T Kovanen

doi:10.1186/1471-2261-9-10

Mikko A Simolin, Mikko I Mäyränpää + Show 5 more

Open Access

https://doi.org/10.1186/1471-2261-9-10

Copy DOI

Abstract

BackgroundWe examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril.MethodsThickening of the aortic valve leaflets in apoE-/- mice was induced by producing mild or moderate chronic renal failure resulting from unilateral nephrectomy (1/2 NX, n = 18) or subtotal nephrectomy (5/6 NX, n = 22), respectively. Additionally, the 5/6 NX mice were randomized to no treatment (n = 8) or enalapril treatment (n = 13). The maximal thickness of each leaflet was measured from histological sections of the aortic roots.ResultsLeaflet thickness was significantly greater in the 5/6 NX mice than in the 1/2 NX mice (P = 0.030) or the unoperated mice (P = 0.003). The 5/6 NX mice treated with enalapril had significantly thinner leaflets than did the untreated 5/6 NX mice (P = 0.014).ConclusionModerate uremia causes thickening of the aortic valves in apoE-/- mice, which can be attenuated by ACE inhibition. The nephrectomized apoE-/- mouse constitutes a new model for investigating the mechanisms of uremia-induced aortic valve disease, and also provides an opportunity to study its pharmacologic prevention.

Highlights

We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril
Angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and Ang II type 1 receptors (AT-1Rs) are expressed in the aortic valves and ACE activity is augmented in the stenotic valves [12,13], suggesting that inappropriate activation of the renin-angiotensin system (RAS) participates in the pathogenesis of aortic stenosis (AS)
Effect of enalapril on aortic valve leaflet thickening in 5/6 NX apoE-/- mice (Study 2) After 36 weeks of uremia, we examined the effect of ACE inhibition on maximal valve thickness in the 5/6 NX apoE-/- mice

Summary

Introduction

We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril. The prevalence of cardiovascular disease (CVD) is far greater in patients with chronic renal failure (CRF) than in the general population [1]. Different mouse models of AS have been tested. These include old apoE-/- mice [18] and old LDLr-/- apoB100/100 mice [19], which are prone to develop functional valvular heart disease, and wild-type mice in which a high fat/high carbohydrate diet was shown to trigger thickening of the aortic valve leaflets [20]

Methods

Results

Discussion

Conclusion