Anti-Inflammatory and Antiproliferative Liver X Receptor Signaling Pathways in Cardiovascular Disease

Cardiovascular disease is the leading cause of morbidity and mortality in industrialized countries. Despite major advances in the treatment of coronary artery disease, most cardiovascular diseases result from complications of atherosclerosis and occlusive vascular disease. The effectiveness of interventional approaches for symptomatic atherosclerotic lesions is limited by vascular smooth muscle cell (VSMC) proliferation leading to in-stent restenosis, bypass graft occlusion and transplant vasculopathy. Thus, an emerging strategy for the treatment of these conditions is to inhibit VSMC activation and proliferation. The liver X receptors (LXR) alpha and beta are important regulators of cholesterol homeostasis and inflammatory pathways in macrophages. Activation of LXRs through synthetic ligands inhibits the development of atherosclerosis in murine models, an effect that is likely to result from the induction of macrophage cholesterol efflux and modulation of both metabolic and inflammatory gene expression. Whether LXRs have a functional role in VSMC is not known. Our preliminary data demonstrate the expression of LXRs in VSMC and identify a previously unrecognized role for LXRs to control VSMC inflammatory gene expression, proliferation and cell cycle progression. Based on these findings our central hypothesis is that LXRs inhibit gene expression critical for VSMC activation and proliferation and ultimately prevent the development of vasculoproliferative diseases. In this proposal, we will utilize both in vitro and in vivo approaches to define the function of LXRs in VSMC. Accordingly we propose to 1) determine the regulation of inflammatory gene expression by LXR activation in VSMC, 2) determine the mechanisms by which LXR activation inhibits VSMC proliferation, 3) determine whether LXR activation prevents neointima formation after mechanical injury in vivo. These experiments may ultimately identify a central role for LXR as a pharmacological target in proliferative cardiovascular diseases and may lead to the development of new therapies to reduce atherosclerosis, postangioplasty restenosis, transplant-vasculopathy and vein-graft failure.