Polo-Like Kinase 1 and Smooth Muscle Cells in Coronary Artery Bypass Conduits and Coronary Arteries Following Angioplasty
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Authors
Sur, Swastika
Issue Date
2016-04-27
Volume
Issue
Type
Dissertation
Language
en_US
Keywords
Alternative Title
Abstract
Objective — An internal mammary artery (IMA) graft is immune to intimal hyperplasia (IH) whereas a saphenous vein (SV) graft is prone to undergo restenosis due to neointima formation. However, the underlying mechanism in vein-graft that makes it prone to stenosis and closure is unknown. In this study, we examined the role of polo-like kinase (PLK)-1 in the PLK1/pPLK1-pCDK1-p-Histone H3 pathway in mediating mitotic progression of smooth muscle cells (SMCs) from human IMA and SV in the development of IH leading to veingraft disease. We also show in vivo data in support of increased immunopositivity towards PLK1 and pPLK1 in SMCs, following percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting that may contribute to greater SMC proliferation in the injured versus uninjured blood vessels in swine.|Approach and Results — At the basal level, higher expression of PLK1 and pPLK1 were noted in SV- than IMA- SMCs. Increased expression and phosphorylation of PLK1 was observed in PDGF-stimulated SV- and IMA-SMCs than their respective controls. Significant increase in PDGF-induced PLK1 mRNA transcript expression was noted in SV- and IMASMCs than their respective controls. The PLK1 inhibitor, BI2536, attenuated PDGF-BBinduced proliferation in IMA and SV-SMCs. BI2536 blocked PDGF-induced CDK1 phosphorylation. Silencing the PLK1 gene by siRNA transfection in SV- and IMA-SMCs attenuated the expression of p-Histone H3. Immunofluorescence staining demonstrated an increase in the number of cells showing immunopositivity to PLK1, pPLK1, p-Histone, IFN-γ and pSTAT-3 in the neointima in post-PTCA coronary arteries and superficial epigastric vein (SEV) grafts.|Conclusions — We are the first to report PLK1 is expressed in VSMCs and a known VSMC stimulant increases the phosphorylation of PLK1 in VSMCs leads to increased phosphorylation of pro-mitotic pCDK1-p-Histone H3 pathway leading to IH. The in vivo data in swine further confirms significantly higher expression of PLK1 and pPLK1 in VSMC present in the hyperplastic intima in post PTCA-coronary arteries and SEV-grafts. Therefore, inhibition of PLK1 activity could be a target in developing better therapeutic approach to prevent VSMC-mediated fibroproliferative diseases.
Description
Citation
Publisher
Creighton University
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Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.