Abstract 16526: Nanoparticle-mediated Targeting of Endothelial mir92a-PPAP2B Signaling Axis in Atherosclerosis

Abstract

Introduction: Atherosclerosis develops preferentially at arterial sites where endothelia are activated by local disturbed hemodynamics. We have recently demonstrated that disturbed flow suppresses PhosPhatidic-Acid-Phosphatase-type-2B (PPAP2B), an integral membrane protein also known as Lipid Phosphate Phosphatase (LPP3) that inactivates lysophosphatidic acid (LPA) and is implicated in coronary artery disease (CAD) by genome-wide association studies. Reduced PPAP2B was detected in athero-susceptible arterial sites exposed to disturbed flow in mice, swine and humans, resulting from elevated miR-92a. PPAP2B inhibition drives the inflammatory and permeable endothelial phenotype by activating LPA-stimulated signalings. Expression quantitative trait locus (eQTL) mapping demonstrated PPAP2B CAD risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells (HAEC). Hypothesis: Given the critical role of PPAP2B in mediating the athero-resistant endothelial phenotype, we test the hypothesis that miR-92a inhibition that elevates PPAP2B can promote vascular health and alleviate atherosclerotic burdens. Novel nanoparticles are designed to spatially target dysfunctional endothelia and deliver miR-92a inhibitors. Methods: Polyelectrolyte complex micelles were engineered to encapsulate charged nucleic acids (miR-92a inhibitors) forming a core by neutralizing their charge. Valine-Histidine-Proline-Lysine-Glutamine-Histidine-Arginine (VHPKQHR), which was identified via phage display and binds vascular endothelial cells through the vascular cell adhesion molecule-1 (VCAM-1), was incorporated to the miRNA inhibitor-containing polyelectrolyte complex micelles to target inflammatory endothelia and facilitate the cellular uptake. Results and Conclusions: We have successfully engineered lesion-targeting polyelectrolyte complex micelles as an innovative delivery system for therapeutic nucleotides and tested their effectiveness in inhibiting miR-92a signaling in vitro in HAEC. Moreover, miR-92a inhibitor-containing micelles significantly reduced the lesion size in ApoE(-/-) mouse model of atherosclerosis in vivo.