Decreased expression of vitamin D receptors in neointimal lesions following coronary artery angioplasty in atherosclerotic swine

Gaurav K. Gupta, Tanupriya Agrawal, Michael Del Core, William J. Hunter, Devendra K. Agrawal

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Inflammatory cytokines, such as TNF-α, play a key role in the pathogenesis of occlusive vascular diseases. Activation of vitamin D receptors (VDR) elicits both growth-inhibitory and anti-inflammatory effects. Here, we investigated the expression of TNF-α and VDR in post-angioplasty coronary artery neointimal lesions of hypercholesterolemic swine and examined the effect of vitamin D deficiency on the development of coronary restenosis. We also examined the effect of calcitriol on cell proliferation and effect of TNF-α on VDR activity and expression in porcine coronary artery smooth muscle cells (PCASMCs) in-vitro. Methodology/Principal Findings: Expression of VDR and TNF-α and the effect of vitamin D deficiency in post-angioplasty coronary arteries were analyzed by immunohistochemistry and histomorphometry. Cell proliferation was examined by thymidine and BrdU incorporation assays in cultured PCASMCs. Effect of TNF-α-stimulation on the activity and expression of VDR was analyzed by luciferase assay, immunoblotting and immunocytochemistry. In-vivo, morphometric analysis of the tissues revealed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased expression of TNF-α in neointimal lesions. Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media. Indeed, post-balloon angioplasty restenosis was significantly higher in vitamin D-deficient hypercholesterolemic swine compared to vitamin D-sufficient group. In-vitro, calcitriol inhibited both serum- and PDGF-BB-induced proliferation in PCASMCs and TNF-α-stimulation significantly decreased the expression and activity of VDR in PCASMCs. Conclusions/Significance: These data suggest that significant downregulation of VDR in proliferating smooth muscle cells in neointimal lesions could be due to atherogenic cytokines, including TNF-α. Vitamin D deficiency potentiates the development of coronary restenosis. Calcitriol has anti-proliferative properties in PCASMCs and these actions are mediated through VDR. This could be a potential mechanism for uncontrolled growth of neointimal cells in injured arteries leading to restenosis.

Original languageEnglish
Article numbere42789
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 6 2012

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Calcitriol Receptors
coronary vessels
vitamin D
Angioplasty
Coronary Vessels
Swine
Muscle
Smooth Muscle Myocytes
smooth muscle
receptors
swine
myocytes
Vitamin D
Vitamin D Deficiency
Calcitriol
vitamin D deficiency
calcitriol
Cells
Coronary Restenosis
Cell proliferation

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Decreased expression of vitamin D receptors in neointimal lesions following coronary artery angioplasty in atherosclerotic swine. / Gupta, Gaurav K.; Agrawal, Tanupriya; Del Core, Michael; Hunter, William J.; Agrawal, Devendra K.

In: PLoS One, Vol. 7, No. 8, e42789, 06.08.2012.

Research output: Contribution to journalArticle

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