A recent study in the Journal of the American Heart Association showed that mice fed a high-fat, high-sucrose (HFHS) diet developed metabolic heart disease through the induction of changes in mitochondrial enzymes by reactive oxygen species (ROS).
Earlier studies in HFHS-fed mice suggested that ROS are involved in the development of metabolic heart disease, but until now, the exact mechanisms have not been known. The study, “Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease,” established a number of mechanisms by which a HFHS diet can cause disease.
The research team, led by Aaron L. Sverdlov from Boston University School of Medicine, fed mice a HFHS diet for four months. As in previous studies using the model, the mice developed metabolic heart disease characterized by left ventricular hypertrophy and diastolic dysfunction.
The team observed that the production of hydrogen peroxide was increased in mitochondria in the heart. The production of ATP, or cellular energy packs, was also decreased, as was the activity of complex II. Complex II is a factor in the energy-producing pathway in mitochondria. The team isolated heart cells from the mice and treated the cells with the reducing agent dithiothreitol. This treatment restored complex II substrate-driven ATP synthesis, suggesting that cysteine amino acids are oxidized in complex II as a result of the diet.
To test this hypothesis, the researchers exchanged two cysteine aminoacids in complex II with serine, which is not sensitive to oxidative modifications. When cells with the modified complex II were grown in a cell culture medium containing high levels of sugar and fat, the team did not observe the complex II dysfunction induced by ROS.
The researchers also exposed transgenic mice to the diet. These mice overexpressed the enzyme catalase, converting hydrogen peroxide to water and oxygen, and hence protecting cells from damage by ROS. After four months on the diet, catalase-overexpressing mice showed much less mitochondrial abnormalities than the normal mice. Signs of heart disease, such as left ventricular hypertrophy and diastolic dysfunction, were also milder in the transgenic mice.
The results demonstrated that efforts to decrease mitochondrial ROS, or their downstream effects on mitochondrial proteins, may be of value in the therapy of metabolic heart disease. The study, however, also underscores the importance of dietary interventions in patients with metabolic syndrome.
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