Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve

Nalini M. Rajamannan, Malayannan Subramaniam, Margaret Springett, Thomas C. Sebo, Marek Niekrasz, Joseph P. McConnell, Ravinder Jit Singh, Neil J. Stone, Robert O. Bonow, Thomas C. Spelsberg

Research output: Contribution to journalArticle

279 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2660-2665
Number of pages6
JournalCirculation
Volume105
Issue number22
DOIs
StatePublished - Jun 5 2002

Fingerprint

Bone Matrix
Osteopontin
Hypercholesterolemia
Nuclear Antigens
Aortic Valve
Osteoblasts
Cholesterol
Cell Proliferation
Rabbits
C-Reactive Protein
Diet
Alkaline Phosphatase
Atherosclerosis
Macrophages
Aortic Valve Stenosis
Hematoxylin
Eosine Yellowish-(YS)
Electron Microscopy
Transcription Factors
Theoretical Models

Keywords

  • Atherosclerosis
  • Cardiovascular diseases
  • Lipids
  • Physiology
  • Valves

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Rajamannan, N. M., Subramaniam, M., Springett, M., Sebo, T. C., Niekrasz, M., McConnell, J. P., ... Spelsberg, T. C. (2002). Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation, 105(22), 2660-2665. https://doi.org/10.1161/01.CIR.0000017435.87463.72

Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. / Rajamannan, Nalini M.; Subramaniam, Malayannan; Springett, Margaret; Sebo, Thomas C.; Niekrasz, Marek; McConnell, Joseph P.; Singh, Ravinder Jit; Stone, Neil J.; Bonow, Robert O.; Spelsberg, Thomas C.

In: Circulation, Vol. 105, No. 22, 05.06.2002, p. 2660-2665.

Research output: Contribution to journalArticle

Rajamannan, NM, Subramaniam, M, Springett, M, Sebo, TC, Niekrasz, M, McConnell, JP, Singh, RJ, Stone, NJ, Bonow, RO & Spelsberg, TC 2002, 'Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve', Circulation, vol. 105, no. 22, pp. 2660-2665. https://doi.org/10.1161/01.CIR.0000017435.87463.72
Rajamannan, Nalini M. ; Subramaniam, Malayannan ; Springett, Margaret ; Sebo, Thomas C. ; Niekrasz, Marek ; McConnell, Joseph P. ; Singh, Ravinder Jit ; Stone, Neil J. ; Bonow, Robert O. ; Spelsberg, Thomas C. / Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. In: Circulation. 2002 ; Vol. 105, No. 22. pp. 2660-2665.
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abstract = "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.",
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AU - Springett, Margaret

AU - Sebo, Thomas C.

AU - Niekrasz, Marek

AU - McConnell, Joseph P.

AU - Singh, Ravinder Jit

AU - Stone, Neil J.

AU - Bonow, Robert O.

AU - Spelsberg, Thomas C.

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