Format

Send to

Choose Destination
Int J Clin Exp Pathol. 2015 May 1;8(5):4639-50. eCollection 2015.

Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1.

Author information

1
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.
2
Department of Obstetrics & Gynecology, Jinan Central Hospital Affiliated to Shandong University Jinan, Shangdong, China.
3
Department of Function Examination, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
4
Department of Pediatrics, Jinan Central Hospital affiliated to Shandong University Jinan, Shangdong, China.
5
Department of Pediatrics, Shandong Provincial Hospital affiliated to Shandong University Jinan, Shangdong, China.

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.

KEYWORDS:

PGC-1α; apoptosis; high glucose; human umbilical vein endothelial cells; mitochondria

PMID:
26191154
PMCID:
PMC4503026
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center