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.
Highlights
Are sent to the cytoplasm by a “retro-translocation mechanism” to be degraded by the ubiquitin proteasome system[20]
To test whether PON1 protein is glycated by high glucose, recombinant PON1 protein was incubated with D-glucose and SDS-PAGE analysis was performed to detect the modifications of PON1 protein by glucose
We have demonstrated that PON1 glycation causes aberrant ER stress via the oxidation of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) in endothelial cells
Summary
Are sent to the cytoplasm by a “retro-translocation mechanism” to be degraded by the ubiquitin proteasome system[20]. ER stress causes the accumulation of unfolded and misfolded proteins, leading to an “unfolded protein response (UPR)”, resulting in cellular dysfunctions[21]. Previous studies have shown that glycation of LDL triggered ER Stress and induced endothelial dysfunction[22,23]. Based on the literature evidence, we hypothesized that PON1 glycation may promote endothelial dysfunction via ER stress. We reported that recombinant PON1 protein was glycated by high glucose in vitro. Glycated PON1 (Gly-PON1) instigated ER stress via the oxidation and inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) in endothelial cells and induced endothelial dysfunction in rats. PON1 glycation is a risk factor of endothelial dysfunction in diabetes
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