Cardiac dysfunction and oxidative stress in the metabolic syndrome: an update on antioxidant therapies

Abstract

The metabolic syndrome (MetS) is a cluster of risk factors including obesity, insulin resistance, dyslipidemia, elevated blood pressure and glucose intolerance. The MetS increases the risk for cardiovascular disease (CVD) and type 2 diabetes. Each component of the MetS causes cardiac dysfunction and their combination carries additional risk. The mechanisms underlying cardiac dysfunction in the MetS are complex and might include lipid accumulation, increased fibrosis and stiffness, altered calcium homeostasis, abnormal autophagy, altered substrate utilization, mitochondrial dysfunction and increased oxidative stress. Mitochondrial and extra-mitochondrial sources of reactive oxygen species (ROS) and reduced antioxidant defense mechanisms characterize the myocardium of humans and animals with the MetS. The mechanisms for increased cardiac oxidative stress in the MetS are not fully understood but include increased fatty acid oxidation, mitochondrial dysfunction and enhanced NADPH oxidase activity. Therapies aimed to reduce oxidative stress and enhance antioxidant defense have been employed to reduce cardiac dysfunction in the MetS in animals. In contrast, large scale clinical trials using antioxidants therapies for the treatment of CVD have been disappointing because of the lack of efficacy and undesired side effects. The focus of this review is to summarize the current knowledge about the mechanisms underlying cardiac dysfunction in the MetS with a special interest in the role of oxidative stress. Finally, we will update the reader on the results obtained with natural antioxidant and mitochondria-targeted antioxidant therapies for the treatment of CVD in the MetS.

Fig. 1. Mechanisms for altered cardiac function in the metabolic syndrome

Common and distinct mechanisms responsible for cardiac dysfunction are highlighted for three important components of the metabolic syndrome; Obesity and dyslipidemia, diabetes and hyperglycemia and insulin resistance.

Fig. 2. Major sites for mitochondrial superoxide (O₂⁻) generation and its detoxification

Black arrows indicate electron flow, blue hatched arrows indicate proton flow and red arrows indicate superoxide production. SOD1 and SOD2: superoxide dismutase 1 and 2; GPx: glutathione peroxidase; Trx: thioredoxin and Grx: glutaredoxin. (The color version of the figure is available in the electronic copy of the article).