Abstract
Interventional procedures, including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG) to re-vascularize occluded coronary arteries, injure the vascular wall and cause endothelial denudation and medial vascular smooth muscle cell (VSMCs) metaplasia. Proliferation of the phenotypically altered SMCs is the key event in the pathogenesis of intimal hyperplasia (IH). Several kinases and phosphatases regulate cell cycle in SMC proliferation. It is our hypothesis that increased expression and activity of polo-like kinase-1 (PLK1) in SMCs, following PTCA and CABG, contributes to greater SMC proliferation in the injured than uninjured blood vessels. Using immunofluorescence (IF), we assessed the expression of PLK1 and phosphorylated-PLK1 (pPLK1) in post-PTCA coronary arteries, and superficial epigastric vein grafts (SEV) and compared it with those in the corresponding uninjured vessels. We also compared the expressions of mitotic marker phospho-histone, synthetic-SMC marker, contractile SMC marker, IFN-γ and phosphorylated STAT-3 in the post-PTCA arteries, SEV-grafts, and the uninjured vessels. Immunostaining demonstrated an increase in the number of cells expressing PLK1 and pPLK1 in the neointima of post PTCA-coronary arteries and SEV-grafts compared to their uninjured counterparts. VSMCs in the neointima showed an increased expression of phospho-histone, synthetic and contractile SMC markers, IFN-γ and phosphorylated STAT-3. However, VSMCs of uninjured coronaries and SEV had no significant expression of the aforementioned proteins. These data suggest that PLK1 might play a critical role in VSMC mitosis in hyperplastic intima of the injured vessels. Thus, novel therapies to inhibit PLK1 could be developed to inhibit the mitogenesis of VSMCs and control neointimal hyperplasia.
Highlights
Cell division, and the progress of cells through their respective cell cycles; are finely regulated and controlled, at specific junctures, by a complex interplay between various kinases and phosphatases
We focused our initial efforts on examining the role of Polo like kinase 1 (PLK1) for several reasons: first, PLK1 functions in activating the major kinases, phosphatases and cyclins that promote mitotic entry and progression through the G2-M cell cycle check point, [29] second, PLK1 overexpression has been well documented in cells with high mitotic index including an SMC tumor, leiomyosarcoma [15], third, a number of small ATP-competitive inhibitors such as BI 2536 and BI 6727, highly selective for PLK 1, are currently in different phases of clinical trial against other common human cancers [30, 31]
We have investigated the presence, expression and activity of PLK1 in Vascular smooth muscle cells (VSMCs), which may play a critical role in the development of intimal hyperplasia (IH) after percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG) in a porcine model
Summary
The progress of cells through their respective cell cycles; are finely regulated and controlled, at specific junctures, by a complex interplay between various kinases and phosphatases. PLK1 has been reported to mediate multiple mitotic processes including centrosome maturation, assembly of the bipolar spindle, chromosome segregation, activation of the anaphase promoting complex (APC/C), and cytokinesis [2,3,4,5,6,7,8,9]. The expression and activity of PLK 1 is elevated in tissues and cells with high mitotic index, such as cancer cells. Ovarian, endometrial, prostate, and colorectal are found to have such elevated expression and activity of PLK1 [10,11,12,13,14]. In 2012, Shan and colleagues [15] reported increased expression of PLK1 and its upstream regulator Aurora A kinase in uterine leiomyosarcomas, a neoplastic lesion involving SMCs of the uterine myometrium. Targeting and inhibition of the PLK1 upstream kinase, Aurora A, in the leiomyosarcomas cells decreased the proliferation and induced apoptosis in these malignant cells [15]
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