Disturbed Flow-Induced Endothelial Proatherogenic Signaling Via Regulating Post-Translational Modifications and...

Hemodynamic shear stress, the frictional force exerted onto the vascular endothelial cell (EC) surface, influences vascular EC functions. Atherosclerotic plaque formation in the endothelium is known to be site specific: disturbed blood flow (d-flow) formed at the lesser curvature of the aortic arch and branch points promotes plaque formation, and steady laminar flow (s-flow) at the greater curvature is atheroprotective.

Post-translational modifications (PTMs), including phosphorylation and SUMOylation, and epigenetic events, including DNA methylation and histone modifications, provide a new perspective on the pathogenesis of atherosclerosis, elucidating how gene expression is altered by d-flow. Activation of PKCζ and p90RSK, SUMOylation of ERK5 and p53, and DNA hypermethylation are uniquely induced by d-flow, but not by s-flow.

Extensive cross talk has been observed among the phosphorylation, SUMOylation, acetylation, and methylation PTMs, as well as among epigenetic events along the cascade of d-flow-induced signaling, from the top (mechanosensory systems) to the bottom (epigenetic events). In addition, PKCζ activation plays a role in regulating SUMOylation-related enzymes of PIAS4, p90RSK activation plays a role in regulating SUMOylation-related enzymes of Sentrin/SUMO-specific protease (SENP)2, and DNA methyltransferase SUMOylation may play a role in d-flow signaling.

Although possible contributions of DNA events such as histone modification and the epigenetic and cytosolic events of PTMs in d-flow signaling have become clearer, determining the interplay of each PTM and epigenetic event will provide a new paradigm to elucidate the difference between d-flow and s-flow and lead to novel therapeutic interventions to inhibit plaque formation. Antioxid. Redox Signal. 25, 435-450.