Decorin mimic inhibits vascular smooth muscle proliferation and migration.

Rebecca A Scott,Alyssa Panitch,Michael Sturek,John E Paderi

doi:10.1371/journal.pone.0082456

Rebecca A Scott, Alyssa Panitch + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0082456

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Abstract

Over the past 10 years, the number of percutaneous coronary intervention procedures performed in the United States increased by 33%; however, restenosis, which inhibits complete functional recovery of the vessel wall, complicates this procedure. A wide range of anti-restenotic therapeutics have been developed, although many elicit non-specific effects that compromise vessel healing. Drawing inspiration from biologically-relevant molecules, our lab developed a mimic of the natural proteoglycan decorin, termed DS-SILY, which can mask exposed collagen and thereby effectively decrease platelet activation, thus contributing to suppression of vascular intimal hyperplasia. Here, we characterize the effects of DS-SILY on both proliferative and quiescent human SMCs to evaluate the potential impact of DS-SILY-SMC interaction on restenosis, and further characterize in vivo platelet interactions. DS-SILY decreased proliferative SMC proliferation and pro-inflammatory cytokine secretion in vitro in a concentration dependent manner as compared to untreated controls. The addition of DS-SILY to in vitro SMC cultures decreased SMC migration and protein synthesis by 95% and 37%, respectively. Furthermore, DS-SILY decreased platelet activation, as well as reduced neointimal hyperplasia by 60%, in vivo using Ossabaw swine. These results indicate that DS-SILY demonstrates multiple biological activities that may all synergistically contribute to an improved treatment paradigm for balloon angioplasty.

Highlights

Percutaneous coronary intervention (PCI) is an invasive cardiovascular procedure performed to mechanically widen narrowed coronary vessels using either balloon angioplasty or intracoronary stenting
For proliferative smooth muscle cells (SMC) cultures, the addition of dermatan sulfate (DS)-SILY20 resulted in decreased proliferation compared to controls, where a significant reduction of SMC proliferation occurred with treatments of 0.1, 1, and 10 μM DSSILY20
While DS-SILY20 elicited a response from proliferative cultures, no change in proliferation was exhibited in quiescent SMC cultures

Summary

Introduction

Percutaneous coronary intervention (PCI) is an invasive cardiovascular procedure performed to mechanically widen narrowed coronary vessels using either balloon angioplasty or intracoronary stenting. While the number of PCI procedures performed in the United States has increased by 33% in the past 10 years[1,2,3], thrombosis, neointimal hyperplasia, and restenosis remain complications of this procedure. The occurrence of these detrimental consequences following PCI is attributed to trauma during the procedure, which triggers an array of mechanical and biological processes implicated in the healing process. PCI often damages the endothelial cells (EC) from the vessel wall, exposing the underlying collagenous layer and providing inherent targets for platelet activation[4,5]. Stimulated SMCs actively participate in the inflammatory cascade, producing and secreting a range of factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)[9,10]

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