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)-β1 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.
Footnotes
-
This work was supported by grants from Osaka City University and Okayama University Medical Research Fund for Medical Research and from the Special Coordination Funds of the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.106.110460.
-
ABBREVIATIONS: CR, calorie restriction; ROS, reactive oxygen species; NO, nitric oxide; OLETF, Otsuka-Long Evans Tokushima Fatty; UCP2, uncoupling protein; MTR, MitoTracker Red; MTG, MitoTracker Green; COX, cytochrome oxidase; eNOS, endothelial nitric-oxide synthase; PAI-1, plasminogen activator inhibitor-1; pVASP, phosphorylated vasodilator-stimulated phosphoprotein; VASP, phosphorylated vasodilator-stimulated phosphoprotein; HNE, 4-hydroxy-2-nonenal; TGF, transforming growth factor; GLUT4, glucose transporter 4; LETO, Long-Evans Tokushima Otsuka; TBS, Tris-buffered saline; TBS-T, TBS-Tween 20; PAGE, polyacrylamide gel electrophoresis; SOD, superoxide dismutase; AP-1, activator protein-1; L-012, 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione.
- Received July 7, 2006.
- Accepted October 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics