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

Abstract

Significance: 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. Recent Advances: 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 PKCf and p90RSK, SUMOylation of ERK5 and p53, and DNA hypermethylation are uniquely induced by d-flow, but not by s-flow. Critical Issues: 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, PKCf 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. Future Directions: 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][436][437][438][439][440][441][442][443][444][445][446][447][448][449][450]

LPS-stimulated Macrophage Activation Affects Endothelial Dysfunction

“…It has been reported that p90RSK overexpression was observed in athero-prone area, where is disturbed flow area and p90RSK expression was colocalized with VCAM-1 expression in endothelium of mouse aorta suggesting that p90RSK plays an inflammatory regulator (5,11,24). To investigate the effect of LPS on endothelial cells-exposed by laminar shear stress, LPSinjected mouse aorta was co-stained with VE-Cad as EC marker and p90RSK in Fig.…”

Injection of hTERT-Transduced Endothelial Progenitor Cells Promotes Beneficial Aortic Changes in a High-Fat Dietary Model of Early Atherosclerosis

“…In particular, Heo et al [23] demonstrated that disturbed laminar flow downregulates endothelial cell production of the enzyme eNOS. As this eNOS downregulation action reduces NO synthesis [24], this process can promote atherosclerotic progression through dysregulating adhesion molecule expression, platelet activation, and vascular smooth muscle activity [25].…”

Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases

“…Upon activation, p90RSK is able to phosphorylate transcription factors such as CREB, NF-κB, and c-fos. In addition, more recent reports indicate phosphorylation of SENP2 and ERK5 by activated p90RSK (Heo et al, 2016, Heo et al, 2015, Le et al, 2013). Activated p90RSK binds the C-terminal transcriptional domain (aa 571–807) of ERK5 and phosphorylates ERK5 S496 with subsequent inhibition of ERK5 transcriptional activity(Le et al, 2013) (Fig.…”

“…For example, atherosclerotic plaque formation has been reported to be localized in the arterial vasculature where ECs experience d-flow(Libby et al, 2002). D-flow occurs at branch points, bifurcations, and curvatures along the arterial tree and not only down-regulates the atheroprotective mechanisms of ECs and vascular reactivity, but also increases EC inflammation (via upregulated expression of leukocyte adhesion molecules), apoptosis, and proliferation(Heo et al, 2016). In contrast, plaque formation is rare in areas exposed to s-flow (10–20 dyn/cm 2 ), which can stimulate ECs to release various factors including NO, PGI 2 , and tPA to inhibit the inflammatory response of leukocytes, coagulation, and proliferation of smooth muscle cells while simultaneously promoting the survival of ECs (Garin et al, 2007, Reinhart-King et al, 2008, Frangos et al, 1985, Di Francesco et al, 2009, Korenaga et al, 1994, Diamond et al, 1989), all of which have anti-atherogenic effects.…”

“…eNOS, endothelial nitric oxide synthesase; KLF, Kruppel-like factor; p90RSK, p90 ribosomal S6 kinase; PKCζ, protein kinase C-ζ; and PPAR, peroxisome proliferator-activated receptor. Reprinted and modified from Heo et al(Heo et al, 2016) with permission of the publisher..…”