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Protective Role of Antioxidants in Diabetes-Induced Cardiac Dysfunction

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Abstract

Cardiac dysfunction occurs during type 1 and type 2 diabetes and results from multiple parameters including glucotoxicity, lipotoxicity, fibrosis and mitochondrial uncoupling. Oxidative stress arises from an imbalance between the production of ROS and the biological system’s ability to readily detoxify the reactive intermediates. It is involved in the etiology of diabetes-induced downregulation of heart function. Several studies have reported beneficial effects of a therapy with antioxidant agents, including trace elements and other antioxidants, against the cardiovascular system consequences of diabetes. Antioxidants act through one of three mechanisms to prevent oxidant-induced cell damages. They can reduce the generation of ROS, scavenge ROS, or interfere with ROS-induced alterations. Modulating mitochondrial activity is an important possibility to control ROS production. Hence, the use of PPARα agonist to reduce fatty acid oxidation and of trace elements such as zinc and selenium as antioxidants, and physical exercise to induce mitochondrial adaptation, contribute to the prevention of diabetes-induced cardiac dysfunction. The paradigm that inhibiting the overproduction of superoxides and peroxides would prevent cardiac dysfunction in diabetes has been difficult to verify using conventional antioxidants like vitamin E. That led to use of catalytic antioxidants such as SOD/CAT mimetics. Moreover, increases in ROS trigger a cascade of pathological events, including activation of MMPs, PPARs and protein O-GlcNAcation. Multiple tools have been developed to counteract these alterations. Hence, well-tuned, balanced and responsive antioxidant defense systems are vital for proper prevention against diabetic damage. This review aims to summarize our present knowledge on various strategies to control oxidative stress and antagonize cardiac dysfunction during diabetes.

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Abbreviations

6PGD:

6-Phosphogluconate dehydrogenase

AGEs:

Advanced glycation end products

ACE:

Angiotensin converting enzyme

AngII:

Angiotensin II

AR:

Aldose reductase

AT1:

Angiotensin II type 1 receptor

CAT:

Catalase

eNOS:

Endothelial nitric oxide synthase

G6PD:

Glucose-6-phosphate dehydrogenase

GR:

Glutathione reductase

GSH:

Glutathione

GSH-Px:

Glutathione peroxidase

GSSG:

Oxidized glutathione

GSSH:

Reduced glutathione

GST:

Glutathione-S-transferase

•OH−:

Hydroxyl radical

H2O2 :

Hydrogen peroxide

iNOS:

Inducible nitric oxide synthase

LV:

Left ventricular

MMPs:

Matrix metalloproteinases

MnSOD/SOD2:

Manganese superoxide dismutase

MT:

Metallothionein

NAC:

N-acetyl-l-cysteine

NADPH:

Nicotinamide adenine dinucleotide phosphate

•NO:

Nitric oxide radical

NOS:

Nitric oxide synthase

NOX:

Nicotinamide adenine dinucleotide phosphate oxidase

NF-κB:

Nuclear factor-kappa B

O2 − :

Oxygen ion

•O2−:

Superoxide radical

PARP:

Poly(ADP-ribose) polymerase

PGC-1α:

PPARγ coactivator-1α

PKA:

Protein kinase A

PKC:

Protein kinase C

PPARs:

Peroxisome proliferator–activated receptors

PPARα, γ:

Peroxisome proliferator–activated receptor α, γ

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

RAS:

Renin–angiotensin system

RyR2:

Ryanodine receptor type 2

SR:

Sarcoplasmic reticulum

SERCA:

Sarco/endoplasmic reticulum Ca2+ ATPase

SOD:

Superoxide dismutase

STZ:

Streptozotocin

TBARS:

Thiobarbituric acid-reactive substances

Trx:

Thioredoxin

Trx-R:

Thioredoxine reductase

Trx-P:

Thioredoxine peroxidase

UCP:

Uncoupling protein

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  1. INSERM U-637, Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve, Montpellier, France

    Guy Vassort

  2. Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey

    Belma Turan

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Correspondence to Belma Turan.

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Vassort, G., Turan, B. Protective Role of Antioxidants in Diabetes-Induced Cardiac Dysfunction. Cardiovasc Toxicol 10, 73–86 (2010). https://doi.org/10.1007/s12012-010-9064-0

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