TNF-α regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1

Abstract

Endothelial dysfunction and monocyte adhesion to vascular endothelial cells are two critical steps in atherosclerosis development, and emerging evidence suggests that protein sialylation is involved in these processes. However, the mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that treatment with the proinflammatory cytokine TNF-α disrupted vascular endothelial cell-cell tight junctions and promoted monocyte endothelial cell adhesion. Western blotting and Sambucus nigra lectin (SNA) blotting analyses revealed that TNF-α treatment decreased α-2, 6-sialic acid transferase 1 (ST6Gal-I) levels and downregulated VE-Cadherin α-2, 6 sialylation. Further analysis demonstrated that TNF-α treatment upregulated β-site amyloid precursor protein enzyme 1 (BACE1) expression, thus resulting in sequential ST6Gal-I proteolytic degradation. Furthermore, our results revealed that PKC signaling cascades were involved in TNF-α-induced BACE1 upregulation. Together, these results indicated that the proinflammatory cytokine TNF-α impairs endothelial tight junctions and promotes monocyte-endothelial cell adhesion by upregulating BACE1 expression through activating PKC signaling and sequentially cleaving ST6Gal-I. Thus, inhibition of BACE1 expression may be a new approach for treating atherosclerosis.

Metastatic cancer cell attachment to endothelium is promoted by endothelial glycocalyx sialic acid degradation

“…∝‐2,6‐linked SA residues exhibited a patchy morphology when compared to WGA‐linked GCX (Figure k). The discontinuity in expression of ∝‐2,6‐linked SA residue was confirmed using orthogonal views of RFPEC monolayers (Figure k) and has also been reported by other studies . When we quantified our observation, coverage of the ECs by the ∝‐2,6‐linked SA residue at baseline conditions (i.e., in the absence of enzyme treatment) was 25.8 ± 5.9% of the RFPEC surface (Figure k), represented by a normalized value of 1.0 ± 0.23 (Figures a and a).…”

Insight in Adhesion Protein Sialylation and Microgravity Dependent Cell Adhesion—An Omics Network Approach

“…SAs of endothelial cells of human umbilical cord veins are suggested to play a role in VE-cadherin organization [52]. Their degree of sialylation is regulated by TNF-alpha [53]. We found VE-cadherin protein in EA.hy926 cells [7].…”

“…As shown above, the status of the sialylation of adhesion proteins depends on the interplay of active sialyltransferases and neuraminidases. In vivo, this interplay can be affected by growth factors, drugs and other physiological components [53,64,65,76,95,115,116]. The expression of neuraminidases is affected by current physiological and pathological conditions [117,118] and has, e.g., an influence on cell apoptosis [119].…”

Can brain impermeable BACE1 inhibitors serve as anti-CAA medicine?

“…At the messenger level, vascular endothelial cells express three alternatively spiced APP mRNA isoforms, APP695, APP751 and APP770, in comparison with neurons that appear to only or predominantly express APP695 [ 72 ]. In cell culture studies, brain microvascular endothelial cells and human umbilical vein endothelial cells are found to express APP, BACE1 and PS1 by immunoblot and immunocytochemical analyses, and can secret Aß into culture medium detectable by ELISA [ 73 – 77 ]. Similar results are obtained from experiments using primary cell cultures prepared from surgically removed human blood vessels [ 25 ].…”

“…Epidemiological studies suggest that many cardiovascular and metabolic conditions are risk factors for dementia of the vascular and AD types, including hypertension, hypotension, hypercholesterolemia, atherosclerosis and diabetes [ 138 – 143 ]. In vitro studies have demonstrated that oxygen and glucose deprivation [ 75 ], proinflammatory cytokines [ 77 ] and high cholesterol [ 144 ] may serve as stress factors to stimulate endothelial Aß production possibly via BACE1 upregulation. The endothelial nitric oxide synthase (eNOS) could participate in modulating the amyloidogenic processing pathway in vascular endothelia [ 74 ].…”