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Review
. 2021 Jun:169:317-342.
doi: 10.1016/j.freeradbiomed.2021.03.046. Epub 2021 Apr 25.

Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy

Nikole J Byrne  1 , Namakkal S Rajasekaran  2 , E Dale Abel  3 , Heiko Bugger  4
Affiliations
Review

Therapeutic potential of targeting oxidative stress in diabetic cardiomyopathy

Nikole J Byrne et al. Free Radic Biol Med. 2021 Jun.

Abstract

Even in the absence of coronary artery disease and hypertension, diabetes mellitus (DM) may increase the risk for heart failure development. This risk evolves from functional and structural alterations induced by diabetes in the heart, a cardiac entity termed diabetic cardiomyopathy (DbCM). Oxidative stress, defined as the imbalance of reactive oxygen species (ROS) has been increasingly proposed to contribute to the development of DbCM. There are several sources of ROS production including the mitochondria, NAD(P)H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. Overproduction of ROS in DbCM is thought to be counterbalanced by elevated antioxidant defense enzymes such as catalase and superoxide dismutase. Excess ROS in the cardiomyocyte results in further ROS production, mitochondrial DNA damage, lipid peroxidation, post-translational modifications of proteins and ultimately cell death and cardiac dysfunction. Furthermore, ROS modulates transcription factors responsible for expression of antioxidant enzymes. Lastly, evidence exists that several pharmacological agents may convey cardiovascular benefit by antioxidant mechanisms. As such, increasing our understanding of the pathways that lead to increased ROS production and impaired antioxidant defense may enable the development of therapeutic strategies against the progression of DbCM. Herein, we review the current knowledge about causes and consequences of ROS in DbCM, as well as the therapeutic potential and strategies of targeting oxidative stress in the diabetic heart.

Keywords: Diabetes; Diabetic cardiomyopathy; Diabetic heart; Mitochondria; Oxidative stress; Reactive oxygen species.

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Figures

Fig. 1.
Fig. 1.. Simplified schematic of A) sources of ROS and B) ROS detoxification by the antioxidant defense system.
Sources of ROS generation in the cardiomyocyte including mitochondrial electron transport chain (ETC), monoamine oxidases (MAO), calpains, nicotinamide adenine dinucleotide (NADH) oxidases (NOX), xanthine oxidase (XO) and uncoupled nitric oxide synthase (NOS). Complex I (NADH dehydrogenase) transfers electrons from NADH and passes to ubiquinone (Q). Complex II (succinate dehydrogenase; SDH) donates electrons from succinate (as part of the Krebs cycle) to Q via FeS clusters. Complex III (cytochrome c oxidoreductase) transfers the electrons carried by ubiquinol (QH2) to cytochrome c (Cyt c). Complex IV (cytochrome c oxidase) transfers electrons (e−) from cytochrome c to O2 to generate water (H2O). Complex V (F1F0 ATP synthase) exchanges protons from the IMS to the matrix, which drives phosphorylation of ADP to form ATP. MAO generates H2O2 and reactive aldehydes as by-products during the oxidation of monoamines. NOX forms a heterodimer with p22phox and produces O2•− upon electron transfer from NADPH to molecular O2. XO reacts with molecular oxygen to produce O2− and H2O2 during the production of uric acid. NOS consumes NADPH and O2 to convert L-arginine to L-citrulline, generating NO and NADP as by-products. I–V: Denotes ETC complex number. B) Generation of ROS is counterbalanced by the antioxidant defense system. Superoxide is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD). H2O2 is converted to H2O by glutathione peroxidase (GSH-Px), peroxiredoxin (PRX) or catalase (CAT). Activity of PRX is regulated by sulfiredoxin (SRX) and thioredoxin (TRX), which is further regulated by TRX reductase (TRXR) and its endogenous inhibitor, thioredoxin interacting protein (TXNIP). Blue indicates active state. Orange indicates inactive state. Intermembrane space (IMS). Proteins have been compartmentalized according to their predominant intracellular localization.
Fig. 2.
Fig. 2.. Targeting ROS-producing and antioxidant enzymes in the diabetic heart.
Enhanced expression/activity of reactive oxygen specifies (ROS)-producing enzymes induces ROS overproduction in the diabetic heart. Although production of ROS is counterbalanced by enhanced expression of the antioxidant defense system, insufficient ROS-detoxification may impair the “redox state” of the diabetic heart, thereby resulting in oxidative stress. Pharmacological inhibition of ROS-producing enzymes or activation of ROS-detoxifying enzymes offers a potential therapeutic approach for the treatment of diabetic cardiomyopathy (DbCM). Green indicates elevated expression/activity in DbCM. Red indicates reduced expression/activity in DbCM. Grey indicates unchanged or unknown expression/activity in DbCM. Blue indicates pharmacological activators/inhibitors. Catalase (CAT); 1-chloro-2,4-dinitrobenzene (CDNB); electron transport chain (ETC); free fatty acid (FFA); glutathione peroxidase (GSH-Px); monoamine oxidase (MAO); nitric oxide oxidase (NOS); nicotinamide adenine dinucleotide phosphate oxidase (NOX); peroxiredoxins (PRX); sulfiredoxin (SRX); superoxide dismutase (SOD); thioredoxin interacting protein (TXNIP); thioredoxin (TRX); TRX reductase (TRXR); xanthine oxidase (XO).
Fig. 3.
Fig. 3.
Consequences of ROS in the diabetic heart. Imbalance of reactive oxygen species (ROS) production and detoxification in the diabetic heart may result in damage to nucleic acids, proteins, and lipids, thereby resulting in mitochondrial dysfunction, myocardial hypertrophy, cell death. The convergence of these mechanisms leads to damage, which contributes to cardiac dysfunction observed in diabetic cardiomyopathy (DbCM). O-GlcNAcylation (O-GlcNAc); mitochondrial DNA (mtDNA).
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