Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve.
OBJECTIVE
To study in a rabbit model the expression of endothelial nitric oxide synthase (eNOS) in association with the development of calcification of the aortic valve, and to assess the effects of atorvastatin on eNOS expression, nitrite concentration, and aortic valve calcification.


METHODS
Rabbits (n = 48) were treated for three months: 16, forming a control group, were fed a normal diet; 16 were fed a 0.5% (wt/wt) high cholesterol diet; and 16 were fed a 0.5% (wt/wt) cholesterol diet plus atorvastatin (2.5 mg/kg/day). The aortic valves were examined with eNOS immunostains and western blotting. Cholesterol and high sensitivity C reactive protein (hsCRP) concentrations were determined by standard assays. Serum nitrite concentrations were measured with a nitric oxide analyser. eNOS was localised by electron microscopy and immunogold labelling. Calcification in the aortic valve was evaluated by micro-computed tomography (CT).


RESULTS
Cholesterol, hsCRP, and aortic valve calcification were increased in the cholesterol fed compared with control animals. Atorvastatin inhibited calcification in the aortic valve as assessed by micro-CT. eNOS protein concentrations were unchanged in the control and cholesterol groups but increased in the atorvastatin treated group. Serum nitrite concentrations were decreased in the hypercholesterolaemic animals and increased in the group treated with atorvastatin.


CONCLUSIONS
These data provide evidence that chronic experimental hypercholesterolaemia produces bone mineralisation in the aortic valve, which is inhibited by atorvastatin.
Rajamannan
N M
NM
Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. n-rajamannan@northwestern.edu
Subramaniam
M
M
Stock
S R
SR
Stone
N J
NJ
Springett
M
M
Ignatiev
K I
KI
McConnell
J P
JP
Singh
R J
RJ
Bonow
R O
RO
Spelsberg
T C
TC
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001021:Aortic Valve / Q000201:enzymology*; D000069059:Atorvastatin; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis; D002114:Calcinosis / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D006349:Heart Valve Diseases / Q000097:blood / Q000201:enzymology / Q000517:prevention & control*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology / Q000517:prevention & control; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits; D014057:Tomography, X-Ray Computed / Q000379:methods
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D009573:Nitrites; D011758:Pyrroles; D002097:C-Reactive Protein; D002784:Cholesterol; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III