
DOI . ORG {
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Title[redir]:
Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy | Diabetologia
Description:
Aims/hypothesis In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDL-induced pericyte loss. Methods Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR. Results Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR. Conclusions/interpretation Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.
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Keywords {🔍}
stress, hogldl, hrcp, ldl, article, google, scholar, pubmed, nldl, cas, diabetes, retinal, cells, fig, oxidative, mitochondrial, protein, apoptosis, cell, diabetic, human, autophagy, dysfunction, levels, polyi, csa, nac, pba, modified, increased, data, retinas, chop, viability, grp, control, effects, pericyte, retinopathy, role, findings, treated, atf, capillary, pericytes, usa, loss, glycated, model, hogldlinduced,
Topics {✒️}
anti-rabbit fluorescence-conjugated antibodies hog-ldl-induced pericyte loss hog-ldl-induced mitochondrial dysfunction inhibit hog-ldl-activated oxidative er-specific pro-apoptotic factor hog-ldl-induced er stress hog-ldl activates p-eif2α mrna-editing catalytic polypeptide altered thrombotic/fibrinolytic balance reactive oxygen species modified low-density lipoproteins ldl-induced pericyte loss stress-induced pericyte loss 78 kda glucose-regulated protein inhibited hog-ldl-induced apoptosis hog-ldl-induced hrcp apoptosis quantitative real-time pcr real-time quantitative pcr oxidized low-density lipoprotein rabbit polyclonal anti-atf6 er stress-related molecules low-density lipoproteins isolated pancreatic beta-cell autophagy lopes-virella mf real-time rt-pcr hog-ldl induced phosphorylation human monocyte-derived macrophages hog-ldl-induced autophagy diabetes-induced mitochondrial dysfunction hog-ldl-induced apoptosis hog-ldl induced apoptosis �highly-oxidised glycated’ ldl intra-retinal oxidised ldl pro-apoptotic factors caspase-3 hog-ldl-induced toxicity hog-ldl-induced effects hog-ldl activated oxidative hypercholesterolaemic stz-diabetic mice pericyte loss induced low density lipoprotein prefix-fixed retinal sections decreased anti-apoptotic bcl-2 decreased membrane potential vitro-modified human ldl jenkins aj kowluru ra inhibit mitochondrial dysfunction measure membrane potential anti-human apob antibodies lipid oxidation products
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headline:Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy
description:In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDL-induced pericyte loss. Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR. Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR. Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.
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Autophagy
Diabetic retinopathy
ER stress
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Modified LDL
Oxidative stress
Pericyte loss
Internal Medicine
Metabolic Diseases
Human Physiology
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headline:Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy
description:In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDL-induced pericyte loss. Human retinal capillary pericytes (HRCP) were exposed to ‘highly-oxidised glycated’ LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR. Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR. Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.
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Diabetic retinopathy
ER stress
Mitochondrial dysfunction
Modified LDL
Oxidative stress
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Internal Medicine
Metabolic Diseases
Human Physiology
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