Glycation of paraoxonase 1 by high glucose instigates endoplasmic reticulum stress to induce endothelial dysfunction in vivo

Abstract

High-density lipoprotein (HDL) modulates low-density lipoprotein and cell membrane oxidation through the action of paraoxonase-1 (PON1). Endoplasmic reticulum (ER) stress has been linked to a wide range of human pathologies including diabetes, obesity, and atherosclerosis. Previous studies have reported that PON1 is glycated in diabetes. The aim of this study is to investigate whether and how PON1 glycation contributes to endothelial dysfunction in diabetes. ER stress markers were monitored by western blot. Endothelial function was determined by organ bath. Incubation of recombinant PON1 proteins with high glucose increased PON1 glycation and reduced PON1 activity. Exposure of HUVECs to glycated PON1 induced prolonged ER stress and reduced SERCA activity, which were abolished by tempol, apocynin, BAPTA, and p67 and p22 siRNAs. Chronic administration of amino guanidine or 4-PBA prevented endothelial dysfunction in STZ-injected rats. Importantly, injection of glycated PON1 but not native PON1 induced aberrant ER stress and endothelial dysfunction in rats, which were attenuated by tempol, BAPTA, and 4-PBA. In conclusion, glycation of PON1 by hyperglycemia induces endothelial dysfunction through ER stress. In perspectives, PON1 glycation is a novel risk factor of hyperglycemia-induced endothelial dysfunction. Therefore, inhibition of oxidative stress, chelating intracellular Ca2+, and ER chaperone would be considered to reduce vascular complications in diabetes.

Endoplasmic reticulum stress‐dependent autophagy inhibits glycated high‐density lipoprotein‐induced macrophage apoptosis by inhibiting CHOP pathway

“…14,16,23 It has been reported that glycation of paraoxonase 1 by high glucose instigates ER stress to induce endothelial dysfunction, and glucolipotoxicity induces THP-1 monocyte apoptosis by up-regulating CHOP expression. 45,46 Our present experiments showed that gly-HDL induced ER stress, as demonstrated by the elevated nuclear translocation of ATF6, phosphorylation of PERK and eIF2α as well as up-regulation of GRP78 and CHOP, which was similar to the effects induced by TM. Conversely, gly-HDL-triggered apoptosis and activation of ER stress-CHOP pathway were suppressed by PBA (an ER stress inhibitor) and the gene silencing of PERK and CHOP.…”

Effect of High Glucose-Induced Oxidative Stress on Paraoxonase 2 Expression and Activity in Caco-2 Cells

“…The effect of glycation on structure and functions of proteins has been widely investigated. Previous studies have shown that PON enzymes are sensitive to glycation triggered by glucose or methylglyoxal (MGO), which induces loss of biological activity [60][61][62]. Even oxidative stress could contribute to alterations of PON2 activity.…”

Interplay between Endoplasmic Reticulum Stress and Large Extracellular Vesicles (Microparticles) in Endothelial Cell Dysfunction

“…When CHOP pathway was inhibited by quercetin, a natural flavonoid known to reduce ER stress, in HUVECs, endothelial function was restored [ 45 ]. Similar to in vitro studies, prolonged administration of PBA attenuated endothelial dysfunction in STZ-induced diabetic rats [ 46 ]. Choi et al [ 47 ] showed also that db / db type-2 diabetic mice had higher protein expression of ER stress markers: BiP, phosphorylated IRE-1α and its downstream XBP-1, phosphorylated PERK and its downstream phosphorylated elF-2α, compared to control animals [ 47 ].…”