1. PIMT prevents the apoptosis of endothelial cells in response to glycated low density lipoproteins and protective effects of grape seed procyanidin B2.
- Author
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Li XL, Li BY, Cheng M, Yu F, Yin WB, Cai Q, Zhang Z, Zhang JH, Wang JF, Zhou RH, and Gao HQ
- 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
- 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., 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., 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.
- Published
- 2013
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