Abstract 104: Endothelial Restoration Of CAD GWAS Gene PLPP3 By Nanomedicine Suppresses Mechano-sensitive YAP/TAZ Activity And Reduces Atherosclerosis In Vivo

Genome-wide association studies (GWAS) have suggested new molecular mechanisms driving vascular complications such as coronary artery disease (CAD). Nevertheless, a major challenge to developing new therapeutic approaches is to spatiotemporally manipulate these GWAS-identified genes in specific vascular tissues of interest in vivo . Atherosclerosis largely occurs in arterial sites where local disturbed flow (DF) activates vascular endothelial cells. The Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) have merged as critical transcriptional regulators responding to biomechanical stimuli. The molecular mechanisms by which DF activates while unidirectional flow (UF) inactivates YAP/TAZ remain incompletely understood. Our recent studies demonstrated that DF and genetic predisposition at the CAD locus 1p32.2 cooperatively suppress endothelial phospholipid phosphatase 3 (PLPP3) transcription by inactivating a mechano-sensitive endothelial enhancer; reduced PLPP3 and consequent activation of lipid lysophosphatidic acid (LPA)-receptor signaling, drive endothelial dysfunction. Here we devised a nanomedicine strategy employing VCAM-1-targeting liposome to preferentially deliver chemically-modified PLPP3 mRNA to inflamed endothelial cells in vivo , effectively suppressing endothelial YAP/TAZ activity and reducing DF-induced atherosclerosis in mice. We discovered a molecular paradigm by which PLPP3 inactivates YAP/TAZ by reducing LPA-induced myosin II and ROCK1. These results highlight a new mechanistic link between GWAS and YAP/TAZ mechano-regulation and moreover, establish the proof of concept of vascular wall-based therapies employing targeted mRNA-based nanomedicine.