4-cresol-sulfate and Atherosclerosis

Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events among CKD patients increase even in cases in which patients undergo hemodialysis, and the mechanisms underlying the so-called "cardiorenal syndrome" are not clearly understood. Recently, small-molecule uremic toxins have been associated with cardiovascular mortality in CKD and/or dialysis patients. These toxins range from small uncharged solutes to large protein-bound structures. In this review, we focused on protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which are poorly removed by current dialysis techniques. Several studies have demonstrated that protein-bound uremic toxins, especially indoxyl sulfate, induce vascular inflammation, endothelial dysfunction, and vascular calcification, which may explain the relatively poor prognosis of CKD and dialysis patients. The aim of this review is to provide novel insights into the effects of indoxyl sulfate and p-cresyl sulfate on the pathogenesis of atherosclerosis.

Topics: Animals; Atherosclerosis; Carbon; Cresols; Humans; Indican; Oxides; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Toxins, Biological; Uremia

The study aimed to explore the effects of p-cresyl sulfate (PCS) of damaging vascular endothelial cells and promoting the formation of atherosclerosis in mice.. The apolipoprotein E (ApoE)-/- mice were fed normally and with a high-fat diet; the ApoE-/- mice fed with high-fat diet were divided into two groups and treated with blank control and PCS, respectively. The aortic arch in each group was taken and underwent the oil red O staining, and the serum PCS content in each group was detected. The basic components of plaque were observed, including foam cells, lipid deposition, and cholesterol crystal. Moreover, human umbilical vein endothelial cells were cultured and divided into control group, PCS treatment group (PCS), PCS treatment with TLR4 overexpression group (PCS+TLR4+), and PCS treatment with TLR4 knock-out group (PCS+TLR4-). The degree of endothelial cell damage was detected using a cluster of differentiation CD42b-/CD31+ endothelial microparticles (EMPs), and expressions of Toll-like receptor 4 (TLR4), triggering receptor expressed on myeloid cells-1 (TREM-1), phosphorylated-endothelial nitric oxide synthase (p-eNOS), and tumor necrosis factor-α (TNF-α) in cells were detected via Polymerase Chain Reaction (PCR) and Western blotting.. The serum PCS concentration in high-fat ApoE-/- mice was increased, and the aortic arch sections of ApoE-/- mice treated with PCS displayed the evident atherosclerotic plaques. Experimental results of human umbilical vein endothelial cells showed that the activity of human umbilical vein endothelial cells treated with PCS declined, the expression levels of TLR4, TREM-1, and TNF-α were increased, while that of p-eNOS was decreased. After the TLR4 knockout, the above effects of PCS were reversed.. PCS damages vascular endothelial cells through TRL4/TREM-1, thereby accelerating the formation of atherosclerosis.

Topics: Animals; Atherosclerosis; Cells, Cultured; Cresols; Human Umbilical Vein Endothelial Cells; Humans; Mice; Nitric Oxide Synthase Type III; Sulfuric Acid Esters; Toll-Like Receptor 4; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

p-cresyl sulfate (PCS) is a protein-bound uremic toxin retained in the blood of patients with chronic kidney disease (CKD) As atherosclerosis is a primary cardiovascular complication for patients with CKD, the aim of the present study was to investigate the mechanisms underlying the aggravation of atherosclerosis by PCS. In addition, the effect of atorvastatin was assessed in reversing the effects of PCS. PCS was revealed to promote the initiation and progression of atherosclerosis. Following treatment with atorvastatin, apolipoprotein E knockout mice demonstrated a reduction in PCS‑induced atherogenesis and plaque vulnerability. In addition, atorvastatin decreased the protein expression levels of vascular cell adhesion molecule‑1 and intercellular cell adhesion molecule‑1, and the interaction between leukocytes and endothelia. The plasma lipid profiles of mice were not significantly affected by gavage of low‑dose atorvastatin. The results of the present study indicate that PCS promotes plaque growth and instability by enhancing leukocyte‑endothelium interaction, and that these effects may be attenuated by atorvastatin treatment.

Topics: Animals; Anticholesteremic Agents; Aorta; Apolipoproteins E; Atherosclerosis; Atorvastatin; Collagen; Cresols; Intercellular Adhesion Molecule-1; Male; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Sulfuric Acid Esters; Vascular Cell Adhesion Molecule-1