Hyperglycemia and Oxidized-LDL exert a deleterious effect on Endothelial Progenitor Cell migration in Type 2 Diabetes Mellitus

doi:10.1016/j.thromres.2010.03.002

Thrombosis Research

Volume 126, Issue 3, September 2010, Pages 166-174

https://doi.org/10.1016/j.thromres.2010.03.002 Get rights and content

Abstract

Introduction

Type 2 diabetes mellitus (DM) patients with coronary artery disease (CAD) have elevated plasma oxidized-LDL (OxLDL) levels and impaired neovascularization. Hyperglycemia and hyperlipidemia impair endothelial progenitor cell (EPC) migration, and endothelial nitric oxide (NO) bioavailability and NO synthase (NOS) activity are essential for EPC migration. Stromal-derived factor-1α (SDF1α) contributes to EPC mobilization and homing by stimulating the CXC receptor-4 (CXCR4) on the EPC plasmalemma to activate the Pi3K/Akt/eNOS signaling pathway. Therefore, we investigated the effect of high glucose (HG) and OxLDL on the migration and NO bioavailability of EPCs from healthy individuals, and then correlated the findings with those of EPCs from type 2 DM patients with and without CAD.

Materials and Methods

EPCs from 15 healthy and 55 patients were exposed to HG, OxLDL, or both before evaluating EPC count, migration and NO production, and expression of CXCR4 and members of Pi3K/Akt/eNOS signaling cascade.

Results

Counts, migration, CXCR4 expression, and NO production were significantly reduced in EPCs from DM and CAD patients compared with that obtained in EPCs from healthy, and were further reduced in DM patients with CAD. The expression of CXCR4 and activation of Pi3K/Akt/eNOS signaling cascade were suppressed in OxLDL- and HG-treated EPCs, and this suppression was exacerbated when EPCs were treated simultaneously with HG and OxLDL.

Conclusions

Hyperglycemia and elevated circulating OxLDL in DM patients with CAD severely impair EPC migration. These results suggest that the underlying mechanism for this impaired EPC migration is linked to the CXCR4/Pi3K/Akt/eNOS signaling pathway.

Section snippets

Subject characteristics

This study comprised 55 type 2 DM patients and 15 age- and sex-matched healthy volunteers, and was approved by the Ethics Committee of the Rambam Health Care Campus. Each participant gave his/her written informed consent. There were three patient groups: 13 type 2 DM patients without CAD (DM), 16 non-diabetic patients with CAD (CAD), and 26 type 2 DM patients with CAD (DM/CAD). The inclusion criterion of the CAD and DM/CAD patients was the finding of ≥ 50% stenosis in at least one major coronary

Subject characteristics

Two DM patients (15%) and five DM/CAD patients (19%) had nephropathy, and three patients in these two groups had retinopathy. The body mass index in the DM and DM/CAD patients was significantly higher than that of the healthy volunteers and CAD patients. The serum cholesterol, LDL, HDL, and creatinine levels were similar in the four groups, but the serum triglyceride levels in the DM/CAD patients were significantly higher than those in the other three groups. The plasma OxLDL levels in the CAD

Discussion

In this study, we demonstrated that the migration of EPCs from type 2 DM and CAD patients is impaired. This impaired EPC migration is exacerbated in type 2 DM patients with CAD who also have a very low EPC count and frequency of CXCR4-positive progenitor cells. We also demonstrated that the combination of HG and OxLDL exerts deleterious effects on EPC migration, NO production, CXCR4 expression, and the Pi3K/Akt/eNOS signaling pathway.

The results of various studies have shown that HG or OxLDL

Sources of funding

This research was supported by grants from the Israel Ministry of Science Culture & Sport, and the Planning and Finance Committee for Higher Education (Saher Hamed), and the Morasha program of the Israel Science Foundation (Grant 1831/07), the Mallat Family Award for Biomedical Research, a San Francisco Diabetes Research Fund, the Samuel Mendel Chodowsky Fund, and the Chief Scientist Office of the Ministry of Health, Israel (Ariel Roguin).

Disclosures

None.

Conflict of interest statement

This piece of the submission is being sent via mail.

Acknowledgments

None.

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In vivo and in vitro studies confirmed that HG induces biochemical and functional changes in endothelium, which causes endothelial cell dysfunction (ECD) (Du et al., 2003). These changes are manifested as a set of functional changes, including a reduction in cell proliferation and viability, which results in an increase in apoptosis, and a reduction in cell migration, which is reflected in impaired wound healing (Hamed et al., 2010; Durak-Kozica et al., 2019). Other important physiological symptoms of endothelial dysfunction are disturbances in the regulation of vasoconstriction and relaxation (Duncan et al., 2008), as well as induction of ischemia and neo-angiogenesis (Mandarino et al., 1994; Durak-Kozica et al., 2019).
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Diabetes-associated hyperglycemia and dyslipidemia are the leading causes of diabetic cardiovascular diseases [3]. In diabetes, glucose levels are associated with increased pathogenic materials, including oxidized low-density lipoprotein (oxLDL) [4]. oxLDL plays an integral role in endothelial dysfunction during the early stage of atherogenesis [5].
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The repair and regeneration of adult tissues is accomplished through the existence and function of stem or progenitor cell populations. With regards to vascular repair, this is accomplished through the use of heterogeneous populations of proangiogenic cells, often called the endothelial progenitor cells (EPCs). In response to hypoxic or inflammatory signals, EPCs are mobilized from storage niches such as the bone marrow, home to site of vascular damage and participate in repair through terminal differentiation or paracrine effects. While the existence of these endothelial reparative cells has been recognized for almost 20 years, an accurate phenotypic description of these cells still remains controversial and complex analytical strategies are required for their identification and functional analysis. Multiple animal and human studies have demonstrated the physiological importance of EPCs, and evidence suggests a paucity of these cells or their dysfunction is correlated with poor vascular health and an increased risk of developing or exacerbating cardiovascular disease. Moreover, the levels and functionality of these cells are particularly sensitive to toxicological exposures and external influences, defining a mechanistic connection between such stimuli and resulting pathology.
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Thereafter, a large number of studies contributed to demonstrate notably in humans that NO also plays a pivotal role in regulating all processes necessary to maintain the functionality of cultured myeloid and circulating putative EPC (Kränkel et al., 2005; Ma, 2006; Chen et al., 2007; Gallagher et al., 2007; Sorrentino et al., 2007; Hamed et al., 2010; Heiss et al., 2010). A reduction in NO bioavailability was observed in both CAC and ECFC cultured in a hyperglycemic medium or isolated from diabetic patients (Kränkel et al., 2005; Chen et al., 2007; Sorrentino et al., 2007; Hamed et al., 2010). This reduction in NO bioavailability is a multifactorial process, resulting from both a decrease in NO production and an increase in NO degradation (Fig. 1).
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Regular ArticleHyperglycemia and Oxidized-LDL exert a deleterious effect on Endothelial Progenitor Cell migration in Type 2 Diabetes Mellitus

Abstract

Introduction

Materials and Methods

Results

Conclusions

Section snippets

Subject characteristics

Subject characteristics

Discussion

Sources of funding

Disclosures

Conflict of interest statement

Acknowledgments

Lab Invest

J Lipid Res

Biochem Biophys Res Commun

J Lipid Res

Atherosclerosis

Metabolism

J Mol Cell Cardiol

J Am Coll Cardiol

Isolation of putative progenitor endothelial cells for angiogenesis

Science

VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells

EMBO J

Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1

Nat Med

Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization

Circulation

Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway

J Cardiovasc Pharmacol

Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease

Circ Res

Altered SDF-1 mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus

J Cell Mol Med

Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells

Nat Med

Nitric oxide differentially regulates proliferation and mobilization of endothelial progenitor cells but not of hematopoietic stem cells

Thromb Haemost

Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke

Stem Cells

Predictive value of circulating oxidized LDL for cardiac events in type 2 diabetic patients with coronary artery disease

Diabetes Care

Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes

Diabetes

High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms

Diabetes

Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes

Diabetes

Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha

J Clin Invest

Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction

Clin Exp Pharmacol Physiol

Regular Article
Hyperglycemia and Oxidized-LDL exert a deleterious effect on Endothelial Progenitor Cell migration in Type 2 Diabetes Mellitus