Abstract 129: Parthenolide Inhibits Inflammatory Dysfunction of Human Aortic Endothelial Cells and Proliferation of Smooth Muscle Cells in vitro and Restenosis in a Rat Model

Abstract

Background: Cardiovascular diseases remain the leading cause of death in developed countries. Endovascular surgical interventions trigger uncontrolled proliferation of smooth muscle cells (SMCs) in the intima (intimal hyperplasia) leading to lumen re-narrowing (restenosis). Despite extensive efforts devoted to therapeutic methods with a focus on inhibiting SMC proliferation, restenosis persists at a significant rate. In recent years, a growing body of knowledge has underscored a crucial role for endothelium damage in the pathophysiology of restenosis, suggesting that preservation of the endothelium would provide an effective approach for effectively curbing restenosis. Methods and Results: We utilized high-throughput screening methods to search for small molecules that could inhibit the proliferation of human aortic SMCs without damaging human aortic endothelial cells (ECs). We identified such a lead compound in Prestwick Library; i.e. Parthenolide, a sesquiterpene lactone extracted from feverfew. Treatment with a low dose (1 μM) of Parthenolide for 96h inhibited SMC but not EC proliferation. When the cells were stimulated with inflammatory cytokines (TNF-α or IL-1β), Parthenolide mitigated cytokine-induced proliferation and MCP-1 production of SMCs, but rescued cytokine-induced endothelial dysfunction, including apoptosis, proliferation, decrease of eNOS, and increase of inflammatory markers. Mechanistic studies showed that while Parthenolide treatment in both SMCs and ECs induced NRF-2 activation (nuclear translocation), NRF-2 knockdown with siRNA diminished the aforementioned beneficial effects of Parthenolide in both cell types. In contrast, NFkB activation was not significantly affected by Parthenolide. In a rat balloon angioplasty model, perivascular delivery of Parthenolide in Pluronic gel effectively inhibited intimal hyperplasia and restenosis 14 days after surgery. Conclusion: These results indicate that the natural compound Parthenolide differentially attenuates pathological behaviors of both human vascular SMCs and ECs, whereas known agents as such are scarce. Thus Parthenolide may serve as a promising lead compound for future development of next-generation anti-restenotic therapeutics.