PIMT Prevents the Apoptosis of Endothelial Cells in Response to Glycated Low Density Lipoproteins and Protective Effects of Grape Seed Procyanidin B2

Xiao-Li Li,Mei Cheng,Jian-Hua Zhang,Rui-Hai Zhou,Wen-Bin Yin,Fei Yu,Hai-Qing Gao,Zhen Zhang,Jun-Fu Wang,Bao-Ying Li,Qian Cai

doi:10.1371/journal.pone.0069979

Abstract

BackgroundThe 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 ResultsHUVEC 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.ConclusionIn 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.

Highlights

Vascular complications remain a leading cause of morbidity and mortality in subjects with diabetes, and experimental evidence suggests that progression of diabetes is associated with profound endothelial dysfunction [1]
In summary, our study identified Protein L-isoaspartyl methyltransferase (PIMT) as a key player responsible for Glycated low density lipoproteins (gly-Low density lipoproteins (LDL)) induced vascular endothelial cells (VEC) apoptosis and grape seed procyanidin B2 (GSPB2) protect against gly-LDL induced VEC apoptosis by PIMT up-regulation
We found that treatment with grape seed procyanidin extracts (GSPE) significantly increased the expression of PIMT in diabetic rats [11]

Summary

Introduction

Vascular complications remain a leading cause of morbidity and mortality in subjects with diabetes, and experimental evidence suggests that progression of diabetes is associated with profound endothelial dysfunction [1]. The endothelium is the active inner monolayer of the blood vessels, forming an interface or barrier between circulating blood in the lumen and the rest of the vessel wall It plays a very important role in maintenance of vascular integrity by protecting the vessels from activation of clotting and proinflammatory factors. In vascular endothelial cells (VEC), gly-LDL increased oxidative stress leading to cellular dysfunction and apoptosis. The molecular mechanism underlying gly-LDL induced endothelial dysfunction and apoptosis remains elusive, which has been the bottle neck in the development of effective therapeutic approaches to the prevention and treatment of diabetic vascular complications [6,7]. Glycated low density lipoproteins (gly-LDL) continuously produced in the setting of diabetic patients play an important role in causing VEC dysfunction and apoptosis. 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

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