Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase
Copyright policy )Activation of protease calpain by oxidized and glycated LDL increases the degradation of endothelial nitric oxide synthase
AbstractOxidation and glycation of low‐density lipoprotein (LDL) promote vascular injury in diabetes; however, the mechanisms underlying this effect remain poorly defined. The present study was conducted to determine the effects of ‘heavily oxidized’ glycated LDL (HOG‐LDL) on endothelial nitric oxide synthase (eNOS) function. Exposure of bovine aortic endothelial cells with HOG‐LDL reduced eNOS protein levels in a concentration‐ and time‐dependent manner, without altering eNOS mRNA levels. Reduced eNOS protein levels were accompanied by an increase in intracellular Ca2+, augmented production of reactive oxygen species (ROS) and induction of Ca2+‐dependent calpain activity. Neither eNOS reduction nor any of these other effects were observed in cells exposed to native LDL. Reduction of intracellular Ca2+ levels abolished eNOS reduction by HOG‐LDL, as did pharmacological or genetic through calcium channel blockers or calcium chelator BAPTA or inhibition of NAD(P)H oxidase (with apocynin) or inhibition of calpain (calpain 1‐specific siRNA). Consistent with these results, HOG‐LDL impaired acetylcholine‐induced endothelium‐dependent vasorelaxation of isolated mouse aortas, and pharmacological inhibition of calpain prevented this effect. HOG‐LDL may impair endothelial function by inducing calpain‐mediated eNOS degradation in a ROS‐ and Ca2+‐dependent manner.
- Queen's University Belfast United Kingdom
- University of Oklahoma Health Sciences Center United States
Glycation End Products, Advanced, Cytoplasm, Proteasome Endopeptidase Complex, Time Factors, Nitric Oxide Synthase Type III, Lipoproteins, Intracellular Space, 610, NADPH Oxidase, Inbred C57BL, Nitric Oxide, LDL, 576, Mice, Genetic, Animals, Humans, Protease Inhibitors, Protein Processing, Calpain, Post-Translational, NADPH Oxidases, Articles, name=SDG 3 - Good Health and Well-being, Enzyme Activation, Lipoproteins, LDL, Mice, Inbred C57BL, Protein Transport, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Calcium, Cattle, Reactive Oxygen Species, Transcription, Protein Processing, Post-Translational
Glycation End Products, Advanced, Cytoplasm, Proteasome Endopeptidase Complex, Time Factors, Nitric Oxide Synthase Type III, Lipoproteins, Intracellular Space, 610, NADPH Oxidase, Inbred C57BL, Nitric Oxide, LDL, 576, Mice, Genetic, Animals, Humans, Protease Inhibitors, Protein Processing, Calpain, Post-Translational, NADPH Oxidases, Articles, name=SDG 3 - Good Health and Well-being, Enzyme Activation, Lipoproteins, LDL, Mice, Inbred C57BL, Protein Transport, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Calcium, Cattle, Reactive Oxygen Species, Transcription, Protein Processing, Post-Translational
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