Integrated proteomics and metabolomics analysis reveals differential lipid metabolism in human umbilical vein endothelial cells under high and low shear stress

Abstract

Atherosclerotic plaque development is closely associated with the hemodynamic forces applied to endothelial cells (ECs). Among these, shear stress (SS) plays a key role in disease development since changes in flow intensity and direction could stimulate an atheroprone or atheroprotective phenotype. ECs under low or oscillatory SS (LSS) show upregulation of inflammatory, adhesion, and cellular permeability molecules. On the contrary, cells under high or laminar SS (HSS) increase their expression of protective and anti-inflammatory factors. The mechanism behind SS regulation of an atheroprotective phenotype is not completely elucidated. Here we used proteomics and metabolomics to better understand the changes in endothelial cells (human umbilical vein endothelial cells) under in vitro LSS and HSS that promote an atheroprone or atheroprotective profile and how these modifications can be connected to atherosclerosis development. Our data showed that lipid metabolism, in special cholesterol metabolism, was downregulated in cells under LSS. The low-density lipoprotein receptor (LDLR) showed significant alterations both at the quantitative expression level as well as regarding posttranslational modifications. Under LSS, LDLR was seen at lower concentrations and with a different glycosylation profile. Finally, modulating LDLR with atorvastatin led to the recapitulation of a HSS metabolic phenotype in EC under LSS. Altogether, our data suggest that there is significant modulation of lipid metabolism in endothelial cells under different SS intensities and that this could contribute to the atheroprone phenotype of LSS. Statin treatment was able to partially recover the protective profile of these cells.

The improvement of the shear stress and oscillatory shear index of coronary arteries during Enhanced External Counterpulsation in patients with coronary heart disease

“…, where surface area near a bifurcation denotes 10mm length from the distal bifurcation to daughter vessels, and surface area of TAWSS � 4 dynes/cm 2 is high-risk area which may induce coronary heart disease [14][15][16][17][18][19]) and SAR-OSI (surface area ratio of high OSI that…”

“…Time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) are well known as primary risk parameters for the development and progression of atherosclerosis [8][9][10][11][12], which can further lead to various types of coronary stenosis [13]. Recent studies have discovered that low TAWSS (� 4 dynes/cm 2 ) and high OSI (� 0.15) are risk factors for ruptureprone phenotype, which may be related to lipid accumulation and inflammatory cell infiltration to the intima [14][15][16][17][18][19]. Therefore, the evaluation of hemodynamic parameters in the epicardial coronary arterial tree is very important for understanding the progression of atherosclerosis as well as high-risk plaque formation.…”

Shear Stress and Metabolic Disorders—Two Sides of the Same Plaque

“…Hypercholesterolemia reduced NO production and vasodilatation in response to shear stress, thus promoting plaque formation in ApoE knockout mice (39,91).On the other hand, shear stress impacts lipid metabolism. For instance, low shear stress disrupted cholesterol metabolism in ECs and upregulated the expression of LDL receptor (168). In ECs, DF and low shear stress activated sterol regulatory element-binding protein (SREBP); the latter is required to increase LDL uptake and fatty acid or cholesterol synthesis (16,113).…”

Applying Proteomics and Integrative “Omics” Strategies to Decipher the Chronic Kidney Disease-Related Atherosclerosis

“…The low-density lipoprotein receptor (LDLR) demonstrated a significant downregulation in its abundance and disturbances in the glycosylation pattern, and the changes were validated by immunohistochemistry and Western blot analysis. Moreover, by utilizing an integrative “omics” approach, a modulation of LDLR with statin was shown to be partially recovering the normal, atheroprotective profile of endothelial cells, thereby pinpointing to a new treatment strategy and demonstrating pleiotropic effect of statin activity [ 56 ].…”