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PIMT prevents the apoptosis of endothelial cells in response to glycated low density lipoproteins and protective effects of grape seed procyanidin B2.
- Source :
-
PloS one [PLoS One] 2013 Jul 26; Vol. 8 (7), pp. e69979. Date of Electronic Publication: 2013 Jul 26 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Background: The development of diabetic angiopathy is associated with profound vascular endothelial cells (VEC) dysfunction and apoptosis. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. However, the underlying molecular mechanism remains largely elusive. Protein L-isoaspartyl methyltransferase (PIMT) is a widely expressed protein repair enzyme by multiple cell types of arterial wall including VEC. Our previous proteomic studies showed that the expression of PIMT was significantly decreased in the aorta of diabetic rats as compared with control rats and treatment with grape seed procyanidin extracts significantly increased the PIMT expression in diabetic rats. We hypothesized that PIMT plays a critical role in gly-LDL induced VEC apoptosis; grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis through PIMT regulation.<br />Methods and Results: HUVEC transfected negative control and PIMT siRNA were treated with or without GSPB2 (10 µmol/L) for 48 h. Moreover, HUVEC of PIMT overexpression were stimulated by gly-LDL (50 µg/ml) in the presence or absence of GSPB2 (10 µmol/L) for 48 h. Our results showed that gly-LDL downregulated PIMT expression and PIMT overexpression or GSPB2 significantly attenuated gly-LDL induced VEC apoptosis. PIMT siRNA increased VEC apoptosis with up-regulation of p53, cytochrome c release, caspase-9 and caspase-3 activation. Mechanistically, overexpression of PIMT or GSPB2 increased the phosphorylation of ERK1/2 and GSK3β in the gly-LDL induced VEC.<br />Conclusion: In summary, our study identified PIMT as a key player responsible for gly-LDL induced VEC apoptosis and GSPB2 protect against gly-LDL induced VEC apoptosis by PIMT up-regulation. Targeting PIMT including use of GSPB2 could be turned into clinical application in the fighting against diabetic vascular complications.
- Subjects :
- Animals
Caspase 3 metabolism
Caspase 9 metabolism
Cell Survival drug effects
Cytochromes c metabolism
Cytosol drug effects
Cytosol metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Glucose pharmacology
Glycation End Products, Advanced
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
Human Umbilical Vein Endothelial Cells drug effects
Humans
In Situ Nick-End Labeling
Phosphorylation drug effects
Plasmids metabolism
RNA, Small Interfering metabolism
Rats
Transduction, Genetic
Transfection
Tumor Suppressor Protein p53 metabolism
Apoptosis drug effects
Biflavonoids pharmacology
Catechin pharmacology
Grape Seed Extract pharmacology
Human Umbilical Vein Endothelial Cells cytology
Human Umbilical Vein Endothelial Cells enzymology
Lipoproteins, LDL pharmacology
Proanthocyanidins pharmacology
Protective Agents pharmacology
Protein D-Aspartate-L-Isoaspartate Methyltransferase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23922881
- Full Text :
- https://doi.org/10.1371/journal.pone.0069979