Effects of calorie restriction on reactive oxygen species production by mitochondrial reverse electron transport, mitochondrial permeability transition pore, and beta-adrenergic stimulation during cardiac hypertrophy

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we addressed the impact of calorie restriction on mitochondria, oxidative stress markers, and {beta}-adrenergic signaling during cardiac hypertrophy. This dietetic intervention prevented cardiac protein elevation, decreased atrial natriuretic peptide levels, and blocked the increase in heart weight per tibia length index seen in isoproterenol-induced cardiac hypertrophy. Our data suggest that inhibition of cardiac pathological growth by calorie restriction is accompanied by a lower mitochondrial reactive oxygen species formation and improved mitochondrial content. We also found that superoxide dismutase and glutathione peroxidase activities negatively correlate with cardiac hypertrophy. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore in mitochondria isolated from isoproterenol-treated mice. Isoproterenol (a {beta}-agonist) increases cardiac rate (chronotropic response) and force of contraction (inotropic response). Given the nature of cardiac hypertrophy induction by isoproterenol, we tested whether calorie restriction could change the cardiac {beta}-adrenergic sensitivity. Using isolated rat hearts in a langendorff system, we found that calorie restriction mice (similar to controls) have preserved {beta}-adrenergic signaling. On the flipside, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to {beta}-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol of isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy. However, it may lack effects on some of the hypertrophic consequences, such as {beta}-adrenergic signaling repression.