Circulation. 2002;105:2660-2665
Published online before print May 13, 2002, doi: 10.1161/01.CIR.0000017435.87463.72
Published online before print May 13, 2002, doi: 10.1161/01.CIR.0000017435.87463.72
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(Circulation. 2002;105:2660.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Atorvastatin Inhibits Hypercholesterolemia-Induced Cellular Proliferation and Bone Matrix Production in the Rabbit Aortic Valve
From the Division of Cardiology, Department of Medicine (N.M.R., N.J.S., R.O.B.), and Center for Comparative Medicine (M.N.), Northwestern University Medical School, Chicago, Ill; and the Department of Biochemistry and Molecular Biology (M. Subramaniam, T.C. Spelsberg), Department of Laboratory Medicine and Pathology (T.C. Sebo, J.M., R.S.), Department of Electron Microscopy (M. Springett), Mayo Clinic, Rochester, Minn.
Correspondence to Nalini M. Rajamannan, MD, Northwestern University Medical School, 201 E Huron St, Suite 10–240, Chicago, IL 60611. E-mail n.rajamannan{at}northwestern.edu
Background— Despite the common occurrence of aortic stenosis, the cellular causes of the disorder are unknown, in part because of the absence of experimental models. We hypothesized that atherosclerosis and early bone matrix expression in the aortic valve occurs secondary to experimental hypercholesterolemia and that treatment with atorvastatin modifies this transformation.
Methods and Results— To test this hypothesis, we developed an experimental hypercholesterolemic rabbit model. New Zealand White rabbits (n=48) were studied: group 1 (n=16), normal diet; group 2 (n=16), 1% (wt/wt) cholesterol diet; and group 3 (n=16), 1% (wt/wt) cholesterol diet plus atorvastatin (3 mg/kg per day). The aortic valves were examined with hematoxylin and eosin stain, Masson trichrome, macrophage (RAM 11), proliferation cell nuclear antigen (PCNA), and osteopontin immunostains. Cholesterol and highly sensitive C-reactive protein (hsCRP) serum levels were obtained by standard assays. Computerized morphometry and digital image analysis were performed for quantifying PCNA (% area). Electron microscopy and immunogold labeling were performed for osteopontin. Semiquantitative RT-PCR was performed for the osteoblast bone markers [alkaline phosphatase, osteopontin, and osteoblast lineage-specific transcription factor (Cbfa-1)]. There was an increase in cholesterol, hsCRP, PCNA, RAM 11, and osteopontin and osteoblast gene markers (alkaline phosphatase, osteopontin, and Cbfa-1) in the cholesterol-fed rabbits compared with control rabbits. All markers except hsCRP were reduced by atorvastatin.
Conclusions— These findings of increased macrophages, PCNA levels, and bone matrix proteins in the aortic valve during experimental hypercholesterolemia provide evidence of a proliferative atherosclerosis–like process in the aortic valve associated with the transformation to an osteoblast-like phenotype that is inhibited by atorvastatin.
Key Words: valves • cardiovascular diseases • lipids • atherosclerosis • physiology
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