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

Gupta GK, Agrawal T, Del Core MG, Hunter WJ, Agrawal DK - PLoS ONE (2012)

Bottom Line: Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences and Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States of America.

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.

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Effect of experimental diets on serum biochemical parameters in female Yucatan MiniSwine.Animals were fed vitamin D-deficient- or vitamin D-sufficient- high cholesterol diets and serum levels of 25-hydroxy vitamin D (A), calcium (B), total cholesterol (C), low density lipoprotein (LDL) (D), and high density lipoprotein (HDL) (E) were measured. Data are shown as mean ± SEM. (N = 8) **P<0.01, ***P<0.001.
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pone-0042789-g002: Effect of experimental diets on serum biochemical parameters in female Yucatan MiniSwine.Animals were fed vitamin D-deficient- or vitamin D-sufficient- high cholesterol diets and serum levels of 25-hydroxy vitamin D (A), calcium (B), total cholesterol (C), low density lipoprotein (LDL) (D), and high density lipoprotein (HDL) (E) were measured. Data are shown as mean ± SEM. (N = 8) **P<0.01, ***P<0.001.

Mentions: To investigate the effect of vitamin D deficiency on the development of restenosis, animals were fed on vitamin D-deficient high cholesterol or vitamin D-sufficient high cholesterol experimental diets. Vitamin D-deficient high cholesterol diet produced significant vitamin D deficiency (Fig. 2A). At the time of euthanasia serum levels of 25(OH) D3, the major circulating form of vitamin D, were significantly decreased in swine on vitamin D-deficient diet (16.67±1.20 ng/ml) compared to swine on vitamin D-sufficient high cholesterol diet (24.33±2.33 ng/ml; p<.01) (Fig. 2A). Vitamin D deficiency did not have any effect on serum calcium levels (Fig. 2B). Experimental diets induced severe hypercholesterolemia in all animals. However, there was no difference in the levels of total serum cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) between the two groups (Fig. 2C–E)).


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

Gupta GK, Agrawal T, Del Core MG, Hunter WJ, Agrawal DK - PLoS ONE (2012)

Effect of experimental diets on serum biochemical parameters in female Yucatan MiniSwine.Animals were fed vitamin D-deficient- or vitamin D-sufficient- high cholesterol diets and serum levels of 25-hydroxy vitamin D (A), calcium (B), total cholesterol (C), low density lipoprotein (LDL) (D), and high density lipoprotein (HDL) (E) were measured. Data are shown as mean ± SEM. (N = 8) **P<0.01, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412822&req=5

pone-0042789-g002: Effect of experimental diets on serum biochemical parameters in female Yucatan MiniSwine.Animals were fed vitamin D-deficient- or vitamin D-sufficient- high cholesterol diets and serum levels of 25-hydroxy vitamin D (A), calcium (B), total cholesterol (C), low density lipoprotein (LDL) (D), and high density lipoprotein (HDL) (E) were measured. Data are shown as mean ± SEM. (N = 8) **P<0.01, ***P<0.001.
Mentions: To investigate the effect of vitamin D deficiency on the development of restenosis, animals were fed on vitamin D-deficient high cholesterol or vitamin D-sufficient high cholesterol experimental diets. Vitamin D-deficient high cholesterol diet produced significant vitamin D deficiency (Fig. 2A). At the time of euthanasia serum levels of 25(OH) D3, the major circulating form of vitamin D, were significantly decreased in swine on vitamin D-deficient diet (16.67±1.20 ng/ml) compared to swine on vitamin D-sufficient high cholesterol diet (24.33±2.33 ng/ml; p<.01) (Fig. 2A). Vitamin D deficiency did not have any effect on serum calcium levels (Fig. 2B). Experimental diets induced severe hypercholesterolemia in all animals. However, there was no difference in the levels of total serum cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) between the two groups (Fig. 2C–E)).

Bottom Line: Interestingly, there was significantly decreased expression of VDR in PCASMCs of neointimal region compared to normal media.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences and Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska, United States of America.

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.

Show MeSH
Related in: MedlinePlus