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.
Keywords: Cardiac dysfunction, mitochondrial dysfunction, reactive oxygen species, antioxidants, oxidative stress, substrate utilization,
metabolic syndrome, insulin resistance.
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