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

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.

Anti-Atherogenic Effect of Hydrogen Sulfide by Over-Expression of Cystathionine Gamma-Lyase (CSE) Gene

“…Tumor suppressor gene p53 plays an important role in protection against atherosclerosis and restenosis [30] . Its expression was found negatively correlated with cell proliferation in human atherosclerosis [31] , but directly associated with increased apoptosis [32] , [33] . With regard to H 2 S, many studies have been suggested that H 2 S up-regulated p53 expression to activate cell apoptosis and inhibit cell growth [34] , [35] , [36] .…”

Protective effects of a grape-supplemented diet in a mouse model of retinal degeneration

“…Specific polyphenol compounds found in grapes, including quercetin, procyanidin B2, resveratrol and epicatechin are bioactive, and can regulate apoptotic, oxidative stress and inflammatory pathways [23]. Molecular targets of grape-derived compounds include key pro-survival molecules, such as glycogen synthase kinase 3β (GSK3β) [24] and the transcription factor STAT3 [25], among many others. Interestingly, modulating both GSK3β and STAT3 has been shown to improve photoreceptor survival [26].…”

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“…Similar results were obtained in ECs using the electronegative LDL subfraction L5 isolated from T2DM patients [ 98 ]. Li et al showed that gLDLs decrease EC survival in a dose-dependent manner by promoting apoptosis [ 99 ]. The authors demonstrated that gLDLs increase p53 nuclear transcription factor levels and activate the glycogen synthase kinase 3 (GSK3b), determining the increase of the cytochrome c release from the mitochondria, which in turn successively activates caspase-9 and the effector caspase-3.…”