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

Simolin MA, Pedersen TX, Bro S, Mäyränpää MI, Helske S, Nielsen LB, Kovanen PT - BMC Cardiovasc Disord (2009)

Bottom Line: 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 maximal thickness of each leaflet was measured from histological sections of the aortic roots.Moderate uremia causes thickening of the aortic valves in apoE-/- mice, which can be attenuated by ACE inhibition.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wihuri Research Institute, Helsinki, Finland. mikko.simolin@helsinki.fi

ABSTRACT

Background: 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.

Methods: Thickening 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.

Results: Leaflet 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).

Conclusion: Moderate 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.

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Relationship between aortic valve leaflet thickening and (A) aortic en face plaque area fraction and (B) the level of plasma creatinine in apoE-/- mice with uremia for 22 weeks (Study 1). N-values, Spearman's correlation coefficients, and P-values are shown.
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Figure 6: Relationship between aortic valve leaflet thickening and (A) aortic en face plaque area fraction and (B) the level of plasma creatinine in apoE-/- mice with uremia for 22 weeks (Study 1). N-values, Spearman's correlation coefficients, and P-values are shown.

Mentions: After exposure to uremia, the aortic leaflets appeared thickened and the leaflet thickening was diffuse, with maximal thickening located in the central third of the leaflet. To quantitate the effect of renal insufficiency on aortic valve thickening, we measured the maximal aortic valve leaflet thickness at the valve nodule in the nephrectomized and control mice. The analysis of leaflet thickness in the mice exposed to uremia for 22 weeks (Study 1) revealed that the thickness of the aortic valve leaflets was significantly greater in the 5/6 NX mice (145 ± 31 μm) than in the 1/2 NX mice (121 ± 31 μm, P = 0.030) or unoperated mice (106 ± 45 μm, P = 0.003) (see Figure 5A). Also, there was a strong correlation between aortic lesional area and aortic valve leaflet thickness (n = 21, Spearman's r = 0.67, P = 0.0009) in the 5/6 NX mice (see Figure 6A). Moreover, plasma creatinine correlated positively with aortic valve leaflet thickness (n = 20, Spearman's r = 0.48, P = 0.034) in the 5/6 NX mice (see Figure 6B). Analysis of leaflet thickness in the mice exposed to uremia for 36 weeks (Study 2) showed a trend of uremia-induced aortic valve thickening, although the result was not statistically significant due to the small number of mice. There was a strong linear correlation between the thickness of the aortic valve leaflets and the total cross-sectional area (P = 0.00000037) (see Figure 3).


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

Simolin MA, Pedersen TX, Bro S, Mäyränpää MI, Helske S, Nielsen LB, Kovanen PT - BMC Cardiovasc Disord (2009)

Relationship between aortic valve leaflet thickening and (A) aortic en face plaque area fraction and (B) the level of plasma creatinine in apoE-/- mice with uremia for 22 weeks (Study 1). N-values, Spearman's correlation coefficients, and P-values are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2663538&req=5

Figure 6: Relationship between aortic valve leaflet thickening and (A) aortic en face plaque area fraction and (B) the level of plasma creatinine in apoE-/- mice with uremia for 22 weeks (Study 1). N-values, Spearman's correlation coefficients, and P-values are shown.
Mentions: After exposure to uremia, the aortic leaflets appeared thickened and the leaflet thickening was diffuse, with maximal thickening located in the central third of the leaflet. To quantitate the effect of renal insufficiency on aortic valve thickening, we measured the maximal aortic valve leaflet thickness at the valve nodule in the nephrectomized and control mice. The analysis of leaflet thickness in the mice exposed to uremia for 22 weeks (Study 1) revealed that the thickness of the aortic valve leaflets was significantly greater in the 5/6 NX mice (145 ± 31 μm) than in the 1/2 NX mice (121 ± 31 μm, P = 0.030) or unoperated mice (106 ± 45 μm, P = 0.003) (see Figure 5A). Also, there was a strong correlation between aortic lesional area and aortic valve leaflet thickness (n = 21, Spearman's r = 0.67, P = 0.0009) in the 5/6 NX mice (see Figure 6A). Moreover, plasma creatinine correlated positively with aortic valve leaflet thickness (n = 20, Spearman's r = 0.48, P = 0.034) in the 5/6 NX mice (see Figure 6B). Analysis of leaflet thickness in the mice exposed to uremia for 36 weeks (Study 2) showed a trend of uremia-induced aortic valve thickening, although the result was not statistically significant due to the small number of mice. There was a strong linear correlation between the thickness of the aortic valve leaflets and the total cross-sectional area (P = 0.00000037) (see Figure 3).

Bottom Line: 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 maximal thickness of each leaflet was measured from histological sections of the aortic roots.Moderate uremia causes thickening of the aortic valves in apoE-/- mice, which can be attenuated by ACE inhibition.

View Article: PubMed Central - HTML - PubMed

Affiliation: Wihuri Research Institute, Helsinki, Finland. mikko.simolin@helsinki.fi

ABSTRACT

Background: 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.

Methods: Thickening 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.

Results: Leaflet 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).

Conclusion: Moderate 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.

Show MeSH
Related in: MedlinePlus