Abstract 618: Targeted Delivery of microRNA-146a/-181b Protects Against Endothelial Dysfunction and Prevents Atherosclerosis

Abstract

Objective: Atherosclerosis, which underlies most cardiovascular diseases (CVD), is a leading cause of mortality and disability in developed countries. The endothelium is an important site of vascular regulation, and its dysfunction initiates atherosclerosis and supports its progression. Current drug therapies, percutaneous angioplasty, and stenting alleviate symptoms but do not reverse atherosclerosis. Thus, more effective strategies that prevent or reverse atherosclerosis via improved endothelial function are needed. Approach: E-selectin serves as a surface marker of inflamed endothelial cells (ECs). We attempted to deliver microRNA (miR)-146a and miR-181b to inflamed endothelium covering atherosclerotic plaques with an E-selectin-targeting multistage vector (ESTA-MSV to inhibit atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and then loaded into ESTA-MSV microparticles. Male apolipoprotein E-deficient mice were fed with Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Results: Atherosclerotic plaque size decreased with treatment of miRs packaged in ESTA-MSV but not in PEG/PEI. Moreover, vascular inflammation markers such as macrophages in aortic root lesion and expression of chemokines in aortic tissues were decreased while the vascular smooth muscle cells and collagen were increased in plaques from ESTA-MSV/miRs-treated mice compared with vehicle-treated group. Systemic delivery of miR-146a/-181b significantly improved the ACh-induced relaxation of aortas and carotid arteries and inhibited ACh-induced endothelium-dependent contraction of carotid arteries of ApoE-/- mice fed with Western diet for 12 weeks Conclusions: Our data demonstrate that the ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates the endothelial dysfunction and prevents atherosclerosis.