Di-(2-ethylhexyl) phthalate limits the pleiotropic effects of statins in chronic kidney disease patients undergoing dialysis and endothelial cells
Journal
Environmental Pollution
Journal Volume
267
Pages
115548
Date Issued
2020
Author(s)
Abstract
The level of di-(2-ethylhexyl) phthalate (DEHP) is elevated in chronic kidney disease patients undergoing dialysis. However, statins are unable to reduce the cardiovascular events in chronic dialysis patients. In this study, we investigated the effects of DEHP on statin-conferred pleiotropic effects and the underlying molecular mechanism in peritoneal dialysis (PD) patients and endothelial cells (ECs). In PD patients with serum DEHP level ?0.0687 μg/mL, statin treatment was not associated with lower risk of cardiovascular disease. In ECs, exposure to DEHP abrogated the simvastatin-induced NO bioavailability and EC-related functions. Additionally, DEHP abolished the anti-inflammatory effect of simvastatin on the tumor necrosis factor α-induced upregulation of adhesion molecules and monocyte adhesion to ECs. Mechanistically, DEHP blunted the activation of transient receptor potential vanilloid type 1 (TRPV1), which is required for NO production by simvastatin in ECs. Notably, DEHP increased the activity and expression of protein phosphatase 2B (PP2B), a negative regulator of TRPV1 activity. The effect of DEHP on PP2B activation was mediated by the activation of the NADPH oxidase/reactive oxygen species (NOX?ROS) pathway. Inhibition of PP2B activity by pharmacological antagonists prevented the inhibitory effects of DEHP on simvastatin-induced Ca2+ influx, NO bioavailability, and EC migration, proliferation, tube formation, and anti-inflammatory action. Collectively, DEHP activates the NOX?ROS?PP2B pathway, which in turns inhibits TRPV1/Ca2+-dependent signaling and abrogates the statin-conferred pleiotropic protection in ECs. ? 2020 The Author(s)
Subjects
DEHP; NO; Pleiotropic effects; PP2B; Statin; TRPV1
SDGs
Other Subjects
Adhesion; Biochemistry; Calcium compounds; Cell death; Chemical activation; Dialysis; Endothelial cells; Esters; Patient treatment; Anti-inflammatory action; Anti-inflammatory effects; Cardio-vascular disease; Cardiovascular event; Chronic kidney disease; Di-2-ethylhexyl phthalate; Transient receptor potential vanilloid; Tumor necrosis factor alpha; Diseases; atorvastatin; calcineurin; endothelial nitric oxide synthase; hydroxymethylglutaryl coenzyme A reductase inhibitor; intercellular adhesion molecule 1; nitric oxide; phthalic acid bis(2 ethylhexyl) ester; reactive oxygen metabolite; reduced nicotinamide adenine dinucleotide phosphate oxidase; rosuvastatin; rovastatin; simvastatin; small interfering RNA; tumor necrosis factor; unclassified drug; vanilloid receptor 1; vascular cell adhesion molecule 1; hydroxymethylglutaryl coenzyme A reductase inhibitor; phthalic acid; phthalic acid bis(2 ethylhexyl) ester; phthalic acid derivative; cell; drug; enzyme activity; phthalate; pleiotropy; reactive oxygen species; adult; aged; antiinflammatory activity; Article; bioavailability; blood level; calcium cell level; calcium signaling; calcium transport; cardiovascular disease; cardiovascular risk; cell adhesion; cell migration; cell proliferation; chronic kidney failure; controlled study; disease association; drug effect; endothelium cell; environmental exposure; enzyme activation; female; heart protection; human; low risk patient; major clinical study; male; monocyte; peritoneal dialysis; pleiotropy; population exposure; protein expression; upregulation; endothelium cell; hemodialysis; Diethylhexyl Phthalate; Endothelial Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phthalic Acids; Renal Dialysis; Renal Insufficiency, Chronic
Publisher
Elsevier Ltd
Type
journal article