Temporal Cross Talk Between Endoplasmic Reticulum and Mitochondria Regulates Oxidative Stress and Mediates Microparticle-Induced Endothelial Dysfunction

Abstract

Aims: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T-cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. Results: Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers XBP-1, p-eIF2alpha and CHOP and nuclear translocation of ATF6 on human aortic endothelial cells. MPs decreased in vitro nitric oxide release by human aortic endothelial cells, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase with siRNA abrogated all MP-mediated effects. Neutralization of Fas-Ligand carried by MPs abolished effects induced by both MP types, whereas neutralization of low density lipoprotein-receptor on endothelial cells prevented T-lymphocyte MP-mediated effects. Innovation and Conclusion: Collectively, endothelial dysfunction triggered by MPs involves temporal cross-talk between ER and mitochondria with respect to spatial regulation of ROS via the neutral sphingomyelinase and interaction of MPs with Fas and/or low density lipoprotein-receptor. These results provide a novel molecular insight into the manner MPs mediate vascular dysfunction and allow identification of potential therapeutic targets to treat vascular complications associated with metabolic syndrome.

Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes

“…ER stress may be mediated by increased oxidative stress and vice-versa 21, 37, 38. Here we sought to determine whether HG and IL-1β perturb ER function in a MAO-dependent manner.…”

“…There is an association between oxidative and ER stress, but whether mitochondrial ROS formation is upstream of ER stress or vice-versa was not clear. Activation of the UPR under stress conditions leads to impaired Ca 2+ and redox homeostasis 21, 38. Hence, oxidative stress is increased leading to impaired mitochondrial function.…”

Paradoxical Effect of Nonalcoholic Red Wine Polyphenol Extract, Provinols™, in the Regulation of Cyclooxygenases in Vessels from Zucker Fatty Rats (fa/fa)

“…The membranes were then washed at least three times in Tris buffer solution containing 0.05% Tween and incubated for 1 hour per wash at room temperature, with the appropriate horseradish peroxidase- (HRP-) conjugated secondary antibody (Amersham). The protein antibody complexes were detected by ECL plus (Amersham) according to the protocol of the manufacturer as previously done [29, 30]. …”

Vésicules extracellulaires, biomarqueurs et bioeffecteurs du syndrome métabolique

“…La contribution des vésicules extracellulaires plasmatiques à la dysfonction endothéliale souvent associée au SMet a été évaluée dans des expériences dans lesquelles des VE isolées à partir du plasma de patients souffrant ou non de SMet ont été injectées par voie intraveineuse à des souris. Dans ces conditions, les VE de patients présentant un SMet, comparées à des VE isolées d'individus sains, induisent chez les souris des altérations de la réponse de l'aorte à l'acétylcholine [29,30]. Cette réponse cellulaire induite par les VE de patients repose sur la voie de signalisation Fas/ligand de Fas [30], à l'origine de la production d'espèces réactives de l'oxygène (ERO) dépendant de l'activation de la sphingomyélinase neutre [29].…”

“…Dans ces conditions, les VE de patients présentant un SMet, comparées à des VE isolées d'individus sains, induisent chez les souris des altérations de la réponse de l'aorte à l'acétylcholine [29,30]. Cette réponse cellulaire induite par les VE de patients repose sur la voie de signalisation Fas/ligand de Fas [30], à l'origine de la production d'espèces réactives de l'oxygène (ERO) dépendant de l'activation de la sphingomyélinase neutre [29]. Par ailleurs, des concentrations élevées de glucose ou d'angiotensine-II augmentent la production de MV endothéliales présentant un potentiel pro-oxydant, pro-coagulant et pro-inflammatoire [31,32].…”