Calorie Restriction Improves Cardiovascular Risk Factors via Reduction of Mitochondrial Reactive Oxygen Species in Type II Diabetic Rats

Abstract

Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. We determined the effects of calorie restriction (CR) on the dynamic aspects of mitochondrial ROS production, UCP2, and the nitric oxide (NO)-cGMP pathway in the cardiovascular tissues of type II diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Some rats were on restricted diets (30% reduction from free intake) from age 29 to 42 weeks. Blood glucose, hemoglobin A1c, plasma levels of free fatty acid, triacylglycerol, and plasminogen activator inhibitor-1 in OLETF rats were significantly higher than those in nondiabetic control [Long-Evans Tokushima Otsuka (LETO)] rats at 29 weeks. Mitochondrial ROS production and UCP2 expression significantly increased in the heart and aorta of OLETF rats compared with those in LETO rats. A fibrogenic growth factor, transforming growth factor (TGF)-␤1 in the coronary vessels, endothelial nitric-oxide synthase, and aortic nitrotyrosine were increased in OLETF rats at 42 weeks. In contrast, an index of the NO-cGMP pathway, phosphorylated vasodilator-stimulated phosphoprotein, and superoxide dismutase activity in the aorta were significantly diminished. The relationship between UCP2 and ROS production in the cardiovascular function of diabetic rats being fed a calorie-restricted diet is unknown. These abnormalities in OLETF rats were reversed to normal levels by CR. CR significantly improved the NO-cGMP pathway via normalizing ROS generation in OLETF rats. A decrease in UCP2 expression by CR may be a compensatory mechanism to counteract decreased intracellular oxidative stress. The data suggest that CR may prevent cardiovascular tissues from oxidative stress provoked by diabetes mellitus.Calorie restriction (CR) is shown to improve some diabetic abnormalities in this article. Cardiovascular disease is prevalent in patients with diabetes mellitus. High blood glucose levels, altered insulin signaling, reactive oxygen species (ROS), inflammation, and protein kinase C activation may lead to a decrease in nitric oxide (NO) bioavailability (Endemann and Schiffrin, 2004). It is well known that diabetes mellitus provokes an increase in oxidative stress in vascular cells and cardiomyocytes. High glucose concentrations, which contribute to the pathogenesis of atherosclerosis in patients with diabetes, lead to intracellular oxidative stress (Baynes, 1991;Baynes and Thorpe, 1999).The Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous type II diabetes, develops hyperglycemic obesity with hyperinsulinemia and insulin resistance after the age of 25 weeks, similar to patients with noninsulindependent diabetes mellitus. In the aorta from OLETF rats,

Role of Glyceraldehyde-Derived AGEs and Mitochondria in Superoxide Production in Femoral Artery of OLETF Rat and Effects of Pravastatin

“…14) However, mitochondrial reactive oxygen species (ROS) were reported to increase in the aortic and cardiac preparations from OLETF rats at 42 weeks of age. 29) Our study confirmed that inhibition of complex II by TTFA reduced superoxide production in the femoral artery of OLETF rats. We also found that GlycerAGEs increased superoxide production in the femoral artery from pravastatin-treated rats and this effect was inhibited by TTFA.…”

The hydrogen sulfide signaling system: changes during aging and the benefits of caloric restriction

“…Furthermore, CR attenuates the age-related impairment of the NO signaling system (Minamiyama et al 2007;Sharifi et al 2008;Yang et al 2004). However, it is unknown whether CR affects the H 2 S signaling system and whether CR specifically attenuates any affects of age on the H 2 S signaling system.…”

The effects of caloric restriction and age on thyroid hormone signalling in the heart of rats

“…Caloric restriction is believed to reduce cardiovascular risk factors and slow down heart aging via reduction of mitochondrial reactive oxygen species in plasma and heart tissues (Minamiyama et al, 2007;Shinmura et al, 2011). On the other hand, several CR effects leading to alterations in gene expression and protein profile and deterioration of heart function have been reported (Katzeff et al, 1997;Sugizaki et al, 2009Sugizaki et al, , 2011Yamagishi et al, 2010).…”