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Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

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Abstract

Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions—either directly or indirectly—leading to ED and CVD.

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Abbreviations

ACh:

Acetylcholine

ADMA:

Asymmetric dimethylarginine

AMPK:

Adenosine monophosphate-dependent kinase

AGEs:

Advanced glycation end products

AG II:

Angiotensin II

AR:

Aldose reductase

ARI:

Aldose reductase inhibitors

BH4 :

Tetrahydrobiopterin

BAD:

Bcl-2-associated death promoter

CRP:

C-reactive protein

CXCR-4:

Chemokine receptor type-4

CVD:

Cardiovascular disease

cGMP:

Cyclic guanosine monophosphate

COX:

Cyclooxygenase

CMKLR1:

Chemokine-like receptor 1

DPP-4:

Dipeptidyl-peptidase-4

DAG:

Diacyl glycerol

ET-1:

Endothelin-1

ED:

Endothelial dysfunction

DDAH:

Dimethylarginine dimethylaminohydrolase

ECs:

Endothelial cells

EPCs:

Endothelial progenitor cells

ERK:

Extracellar signal-regulated kinases

EDHF:

Endothelium-derived hyperpolarizing factor

eNOS:

Endothelial NO synthase

FAD:

Flavin adenine dinucleotide

FMN:

Flavin mononucleotide

FOXO3a:

Forkhead transcription factor3a

GTP:

Guanosine triphosphate

GC:

Guanylate cyclase

GSH:

Glutathione

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GA-3P:

Glyceraldehyde-3-phosphate

G-6-Pase:

Glucose-6-phosphatase

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide-1

HDL:

High density lipoprotein

HIF-1α:

Hypoxia-inducible factor-1α

HFD:

High fat diet

HUVECs:

Human umbilical vein endothelial cells

HO-1:

Heme oxygenase-1

HSP:

Hexosamine synthetic pathway

HSL:

Hormone sensitive lipase

IR:

Insulin resistance

IKK:

Inhibitor of κB kinase

IRS:

Insulin receptor substrate

IGF-I:

Insulin growth factor

ICAM-1:

Intercellular adhesion molecule-1

JNK:

c-Jun N-terminal kinases

JAM-A:

Junction adhesion molecule A

LDL:

Low density lipoprotein

L-NAME:

Nitro-l-arginine methyl ester

LOX-1:

Lecithin-like ox-LDL receptor-1

LC:

Lactosyl ceramide

MMP-9:

Matrix metallopeptidase-9

MAPK:

Mitogen activated protein kinase

MCP-1:

Monocyte chemotactic protein-1

MnSOD:

Mn superoxide dismutase

MPO:

Myeloperoxidase

MDA:

Malondialdehyde

NF-κB:

Nuclear factor κB

NO:

Nitric oxide

NEFA:

Non-esterified fatty acids

Nox:

NADPH oxidase

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

NIK:

NF-kB inducing kinase

Nampt:

Nicotinamide phosphoribosyltransferase

PTEN:

Phosphatase and tensin homolog

PK:

Protein kinase

PI3K/Akt:

Phosphatidylinositol triphosphate kinase/Akt (protein kinase B)

PKC:

Protein kinase C

PTPs:

Protein tyrosine phosphatases

PON-1:

Paraoxonase-1

PGI2 :

Prostacyclin

PSGL:

P-selectin glycoprotein ligand

PPARγ:

Peroxisome proliferator activated receptor

PARP:

Poly (ADP-ribose) polymerase

PDGF:

Platelet-derived growth factor

PLC:

Phospholipase C

PAI:

Plasminogen activator inhibitor

PGC:

Peroxisome proliferator activated receptor γ coactivator

PEPCK:

Phosphoenolpyruvate carboxykinase

ROS:

Reactive oxygen species

RAGE:

Receptors for advanced glycated end products

STAT:

Signal transducer and activator of transcription

SDF-1:

Stromal cell-derived factor-1

S1P:

Sphingosine-1-phosphate

SK:

Sphingosine kinase

SOD:

Superoxide dismutase

SDH:

Sorbitol dehydrogenase

SOCS-3:

Supressor of cytokine signaling 3

SHP:

Src-homology-2 domain-containing phosphatase

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

TNF-α:

Tumor necrosis factor-α

TNFR:

Tumor necrosis factor receptor

TRAF:

TNFR-associated factor

TRADD:

TNF receptor-associated death domain

TGF:

Transforming growth factor

TXA2 :

Thromboxane A2

tPA:

Tissue plasminogen activator

UDP-GlcNAc:

UDP-N-acetylglucosamine

UCP:

Uncoupling protein

VLDL:

Very low density lipoprotein

VSMCs:

Vascular smooth muscle cells

VEGF:

Vascular endothelial growth factor

VCAM:

Vascular cell adhesion molecule

XRCC1:

X-ray repair cross-complementing protein-1

ZO:

Zucker obese rats

ZL:

Zucker lean rats

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Acknowledgments

The authors would like to thank Dr. Maha Mahmoud Samy for her valuable assistance.

Authors’ Contribution

MIS, MAK, and HD designed and edited this review. MIS, TMA, and MMS wrote this review. MY and SHT critically revised this review and helped in literature search and data collection. All the authors have read and approved the final version of this review.

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Authors and Affiliations

  1. Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt

    Mohamed I. Saad & Maher A. Kamel

  2. Hudson Institute of Medical Research, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia

    Mohamed I. Saad

  3. Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt

    Taha M. Abdelkhalek & Moustafa M. Saleh

  4. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Mina Youssef

  5. Department of Molecular Medicine, University of Padova, Padua, Italy

    Shady H. Tawfik

  6. Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark

    Helena Dominguez

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  1. Mohamed I. Saad
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Saad, M.I., Abdelkhalek, T.M., Saleh, M.M. et al. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells. Endocrine 50, 537–567 (2015). https://doi.org/10.1007/s12020-015-0709-4

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