title: Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1.
abstract: Endothelial cells (ECs) apoptosis induced by hyperglycemia is intimately involved in the pathophysiology of diabetes and its complication. Although PGC-1α is known for its role in glucose metabolism, its role in ECs injury caused by high glucose milieu is still unclear. Therefore, this study aims to investigate whether PGC-1α participates in ECs apoptosis under high glucose condition. Human umbilical vein endothelial cells (HUVECs) were down-regulated PGC-1α expression by adenovirus-mediated PGC-1α specific siRNA (Ad-shPGC-1α) and exposed to high glucose. Cell viability, apoptosis, mitochondrial membrane permeability, apoptotic marker, reactive oxygen species (ROS), and expression of PGC-1α and VDAC isoforms were studied. Our results showed that high glucose-induced cell apoptosis was associated with an obvious decrease in PGC-1α expression. Lack of PGC-1α exacerbated high glucose-induced cell apoptosis, inner mitochondrial membrane permeabilization, mitochondrial cytochrome c release into cytoplasm and caspases activation; while further decreased cell viability and mitochondrial membrane potential. Analysis of apoptotic markers (Bcl-2, Bax), intracellular ROS and endoplasmic reticulum stress revealed that these mechanisms were not accounted for the effects of Ad-shPGC-1α on apoptosis. However, we found silencing PGC-1α further increased high glucose-induced VDAC1 expression. The pharmacological inhibition of VDAC1 with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited the increased apoptosis in high glucose-treated PGC-1α knockdown cells. These findings strongly suggest that PGC-1α defect is one of the major mechanisms for ECs apoptosis under high glucose condition, and provide a novel strategy to prevent endothelial dysfunction in diabetes.
authors.affiliation: Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University Jinan, Shangdong, China ; Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Obstetrics & Gynecology, Jinan Central Hospital Affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Function Examination, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University Jinan, Shangdong, China.
authors.forename: Guimei
authors.initials: G
authors.lastname: Li
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D005947:Glucose / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010539:Permeability; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014162:Transfection; D050995:Voltage-Dependent Anion Channel 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D005947:Glucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid
keywords: PGC-1α; apoptosis; high glucose; human umbilical vein endothelial cells; mitochondria