Glycocalyx sialic acids regulate Nrf2-mediated signaling by fluid shear stress in human endothelial cells

Abstract

Activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway is critical for vascular endothelial redox homeostasis in regions of high, unidirectional shear stress (USS), however the underlying mechanosensitive mediators are not fully understood. The endothelial glycocalyx is disrupted in arterial areas exposed to disturbed blood flow that also exhibit enhanced oxidative stress leading to atherogenesis. We investigated the contribution of glycocalyx sialic acids (SIA) to Nrf2 signaling in human endothelial cells (EC) exposed to atheroprotective USS or atherogenic low oscillatory shear stress (OSS). Cells exposed to USS exhibited a thicker glycocalyx and enhanced turnover of SIA which was reduced in cells cultured under OSS. Physiological USS, but not disturbed OSS, enhanced Nrf2-mediated expression of antioxidant enzymes, which was attenuated following SIA cleavage with exogenous neuraminidase. SIA removal disrupted kinase signaling involved in the nuclear accumulation of Nrf2 elicited by USS and promoted mitochondrial reactive oxygen species accumulation. Notably, knockdown of the endogenous sialidase NEU1 potentiated Nrf2 target gene expression, directly implicating SIA in regulation of Nrf2 signaling by USS. In the absence of SIA, deficits in Nrf2 responses to physiological flow were also associated with a pro-inflammatory EC phenotype. This study demonstrates that the glycocalyx modulates endothelial redox state in response to shear stress and provides the first evidence of an atheroprotective synergism between SIA and Nrf2 antioxidant signaling. The endothelial glycocalyx therefore represents a potential therapeutic target against EC dysfunction in cardiovascular disease and redox dyshomeostasis in ageing.

Syndecan-1 Shedding by Matrix Metalloproteinase-9 Signaling Regulates Alveolar Epithelial Tight Junction in Lipopolysaccharide-Induced Early Acute Lung Injury

“…SDC-1 in the glycocalyx plays an important role in response to ischemia-reperfusion injury, hyperglycemia, endotoxemia, septic shock, and abnormal blood shear stress. [21][22][23][24] Chen et al also showed that pretreatment with NAH protects HS shedding from the intestinal mucosal surfaces in cecal ligation and perforation-induced mouse septic intestinal injury. 25 The results in the present study showed that downregulation of MMP-9 is significantly protected against LPS-induced SDC-1 shedding, thereby reducing the damage to tight junction.…”

In Sickness and in Health: The Oxygen Reactive Species and the Bone

“…Literature concerning the role of oxidative stress in mechanotransduction and adaptive responses in endothelial cells is more abundant and allows a better understanding of both the mechanical forces involved and the cellular response ( Hsieh et al, 2014 ; Chatterjee, 2018 ; Roux et al, 2020 ; Psefteli et al, 2021 ). Some studies in cartilage also contribute to the characterization of mechanical loading and redox state alterations ( Coleman et al, 2017 ; Walsh et al, 2019 ), with evidence supporting that inflammation induced by mechanical loading is ROS-mediated ( Kamalathevan et al, 2021 ).…”

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

“…This negatively-charged hair/gel-like surface layer comprises glycoproteins (syndecan, glycipan, CD44) with glucosaminoglycan side-chains (heparan sulfate, chrondroitin sulfate), long-chain hyaluronic acid and glycolipids; it regulates fluid homeostasis, albumin transcytosis (218) and permeability (455), and minimises adhesion and emigration of blood cells. Glycocalyx sialic acid residues regulate EC redox state via modulation of shear stress-induced Nrf2-mediated signaling (331). This is of relevance considering that sialic acids are emerging as important players in the pathophysiology of SARS-CoV-2 (330), their incorporation into cell membranes is influenced by the diet (see nutrition section) and linked to complex immune responses (318).…”