PT  - JOURNAL ARTICLE
AU  - Jiayu Zhu
AU  - Chih-Fan Yeh
AU  - Ru-Ting Huang
AU  - Tzu-Han Lee
AU  - Tzu-Pin Shentu
AU  - David Wu
AU  - Kai-Chien Yang
AU  - Yun Fang
TI  - Endothelial restoration of CAD GWAS gene PLPP3 by nanomedicine suppresses YAP/TAZ activity and reduces atherosclerosis <em>in vivo</em>
AID  - 10.1101/2021.05.06.443006
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.06.443006
4099  - http://biorxiv.org/content/early/2021/05/07/2021.05.06.443006.short
4100  - http://biorxiv.org/content/early/2021/05/07/2021.05.06.443006.full
AB  - Genome-wide association studies (GWAS) have suggested new molecular mechanisms in vascular cells driving atherosclerotic diseases such as coronary artery disease (CAD) and ischemic stroke (IS). Nevertheless, a major challenge to develop new therapeutic approaches is to spatiotemporally manipulate these GWAS-identified genes in specific vascular tissues in vivo. YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) have merged as critical transcriptional regulators in cells responding to biomechanical stimuli, such as in athero-susceptible endothelial cells activated by disturbed flow (DF). The molecular mechanisms by which DF activates while unidirectional flow (UF) inactivates YAP/TAZ remain incompletely understood. Recent studies demonstrated that DF and genetic predisposition (risk allele) of CAD/IS locus 1p32.2 converge to reduce phospholipid phosphatase 3 (PLPP3) expression in vascular endothelium. Restoration of endothelial PLPP3 in vivo, although remains challenging and unexplored, is hypothesized to reduce atherosclerosis. We devised a nanomedicine system integrating nanoparticles and Cdh5 promoter-driven plasmids to successfully restore PLPP3 expression in activated endothelium, resulting in suppressed YAP/TAZ activity and reduced DF-induced atherosclerosis in mice. Mechanistically, our studies discovered a molecular paradigm by which CAD/IS GWAS gene PLPP3 inactivates YAP/TAZ by reducing lysophosphatidic acid (LPA)-induced myosin II and ROCK in endothelium under UF. These results highlight a new mechanistic link between GWAS and YAP/TAZ mechano-regulation and moreover, establish a proof of concept of vascular wall-based therapies employing targeted nanomedicine to manipulate CAD/IS GWAS genes in vivo.Competing Interest StatementThe authors have declared no competing interest.