Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 320, Issue 2, Pages 535-543Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.110460
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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)-beta 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.
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