Abstract
BackgroundInflammatory 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 FindingsExpression 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/SignificanceThese 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.
Highlights
Percutaneous coronary intervention is a common strategy to treat coronary artery disease but, neointimal hyperplasia with resultant restenosis following interventional procedure remains the major limitation [1,2]
We investigated the effect of calcitriol on cell proliferation in porcine coronary artery smooth muscle cells (PCASMCs)
Previous studies have demonstrated that vitamin D and its analogues are involved in the inhibition of vascular smooth muscle cells (VSMCs) proliferation
Summary
Percutaneous coronary intervention is a common strategy to treat coronary artery disease but, neointimal hyperplasia with resultant restenosis following interventional procedure remains the major limitation [1,2]. Neointimal hyperplasia, a cell proliferation and differentiation process, is the predominant mechanism in the development of in-stent restenosis and anti-proliferative drugs in DES suppress tissue re-growth [2]. There is marked increase in tissue expression of TNF-a due to arterial injury following balloon angioplasty [6]. Inflammatory cytokines, such as TNF-a, play a key role in the pathogenesis of occlusive vascular diseases. We investigated the expression of TNF-a 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 examined the effect of calcitriol on cell proliferation and effect of TNF-a on VDR activity and expression in porcine coronary artery smooth muscle cells (PCASMCs) in-vitro
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
