Abstract 427: Flow Regulation of YAP/TAZ in Endothelial Inflammation and Atherosclerosis
The focal nature of atherosclerotic lesions in regions such as arterial branch points and curvatures suggests a regulatory mechanism by local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechano-transduction and vascular homeostasis. However, the mechanism by which YAP/TAZ modulates endothelial phenotypes in response to atheroprone vs. atheroprotective hemodynamic flows remains unknown. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of endothelial inflammation and the consequential development of atherosclerotic lesions.
Experiments were conducted on cultured vascular endothelial cells (ECs) and atherosclerotic mouse model. We found that exposure of ECs to the atheroprone oscillatory shear stress (OS) results in YAP/TAZ activation and translocation into EC nucleus to upregulate the target genes, including connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (Cyr61). In contrast, the atheroprotective laminar shear stress suppresses YAP/TAZ. Consistent with these in vitro results, ex vivo analysis of mouse arteries demonstrated a more nuclear localization of YAP/TAZ and elevated levels of CTGF and Cyr61 in the endothelium in atheroprone areas than in atheroprotective areas. Functionally, YAP/TAZ knockdown significantly attenuated the OS- and cytokine-inductions of pro-inflammatory adhesion molecules in ECs and monocytes, as well as the consequential monocyte adhesion to ECs. Overexpression of constitutively active YAP increases endothelial inflammation and monocyte adhesion to ECs. Furthermore, in vivo blockade of YAP/TAZ translation by Morpholino oligos in apolipoprotein E-deficient mice significantly reduced endothelial inflammation, mononuclear cell infiltration, and the size of atherosclerotic plaques.
Our results demonstrate a critical role of YAP/TAZ activation by atheroprone flow in promoting endothelial inflammation and the development of atherosclerotic lesions. Therefore, inhibition of YAP/TAZ activation may hold promise as a novel atheroprotective therapeutic strategy.
Author Disclosures: K. Wang: None. P. Nguyen: None. E. Limqueco: None. Y. Li: None. S. Chien: None.
- © 2015 by American Heart Association, Inc.