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Hyperuricemia-induced endothelial insulin resistance: the nitric oxide connection

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Abstract

Hyperuricemia, defined as elevated serum concentrations of uric acid (UA) above 416 µmol L−1, is related to the development of cardiometabolic disorders, probably via induction of endothelial dysfunction. Hyperuricemia causes endothelial dysfunction via induction of cell apoptosis, oxidative stress, and inflammation; however, it's interfering with insulin signaling and decreased endothelial nitric oxide (NO) availability, resulting in the development of endothelial insulin resistance, which seems to be a major underlying mechanism for hyperuricemia-induced endothelial dysfunction. Here, we elaborate on how hyperuricemia induces endothelial insulin resistance through the disruption of insulin-stimulated endothelial NO synthesis. High UA concentrations decrease insulin-induced NO synthesis within the endothelial cells by interfering with insulin signaling at either the receptor or post-receptor levels (i.e., proximal and distal steps). At the proximal post-receptor level, UA impairs the function of the insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) in the insulin signaling pathway. At the distal level, high UA concentrations impair endothelial NO synthase (eNOS)-NO system by decreasing eNOS expression and activity as well as by direct inactivation of NO. Clinically, UA-induced endothelial insulin resistance is translated into impaired endothelial function, impaired NO-dependent vasodilation, and the development of systemic insulin resistance. UA-lowering drugs may improve endothelial function in subjects with hyperuricemia.

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Abbreviations

ABC:

ATP-binding cassette transporter

Ang-II:

Angiotensin II

AP-1:

Activator protein-1

BCRP:

Breast cancer resistance protein

CI:

Confidence interval

eNOS:

Endothelial nitric oxide synthase

ENPP1:

Ectonucleotide pyrophosphatase/phosphodiesterase 1

ERK:

Extracellular signal-regulated kinase

ET-1:

Endothelin-1

GLUT:

Glucose transporter

HPX:

Hypoxanthine

HUVEC:

Human umbilical vein endothelial cell

IRS:

Insulin receptor substrate

JNK:

C-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MCT:

Monocarboxylate transporter

MRP:

Multidrug resistance-associated protein

NF-κB:

Nuclear factor kappa-B

NO:

Nitric oxide

OAT:

Organic anion transporter

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

ROS:

Reactive oxygen species

RR:

Relative risk

SLC:

Solute carrier family

T2DM:

Type 2 diabetes mellitus

UA:

Uric acid

UAT:

Uric acid transporter

URATv1:

Voltage-driven urate transporter 1

VCAM-1:

Vascular cell adhesion molecule-1

XDH:

Xanthine dehydrogenase

XO:

Xanthine oxidase

XOR:

Xanthine oxidoreductase

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Funding

This study has been supported by Shahid Beheshti University of Medical Sciences (Grant Number 25401), Tehran, Iran.

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Authors and Affiliations

  1. Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Zahra Bahadoran & Parvin Mirmiran

  2. Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA

    Khosrow Kashfi

  3. Graduate Program in Biology, City University of New York Graduate Center, New York, NY, 10016, USA

    Khosrow Kashfi

  4. Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, No. 24, Parvaneh Street, P.O. Box: 19395-4763, VelenjakTehran, Iran

    Asghar Ghasemi

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Idea and conceptualization: Asghar Ghasemi and Zahra Bahadoran

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This article is part of the special issue on pathophysiological mechanisms of cardiometabolic diseases in Pflügers Archiv—European Journal of Physiology

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Bahadoran, Z., Mirmiran, P., Kashfi, K. et al. Hyperuricemia-induced endothelial insulin resistance: the nitric oxide connection. Pflugers Arch - Eur J Physiol 474, 83–98 (2022). https://doi.org/10.1007/s00424-021-02606-2

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