Minamiyama Yukiko, Bito Yasuyuki, Takemura Shigekazu, Takahashi Yosuke, Kodai Shintaro, Mizuguchi Shinjiro, Nishikawa Yuriko, Suehiro Shigefumi, Okada Shigeru
Department of Anti-Aging Food Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Shikata-cho, Okayama 700-8558, Japan.
J Pharmacol Exp Ther. 2007 Feb;320(2):535-43. doi: 10.1124/jpet.106.110460. Epub 2006 Oct 26.
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)-beta1 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.
解偶联蛋白2（UCP2）是细胞内活性氧（ROS）生成的重要调节因子。我们确定了热量限制（CR）对II型糖尿病大冢长- Evans -德岛肥胖（OLETF）大鼠心血管组织中线粒体ROS生成、UCP2以及一氧化氮（NO）-环磷酸鸟苷（cGMP）途径动态变化的影响。一些大鼠从29周龄到42周龄接受限制饮食（比自由摄入量减少30%）。29周时，OLETF大鼠的血糖、糖化血红蛋白、游离脂肪酸、三酰甘油和纤溶酶原激活物抑制剂-1的血浆水平显著高于非糖尿病对照[大冢长- Evans -德岛（LETO）]大鼠。与LETO大鼠相比，OLETF大鼠心脏和主动脉中的线粒体ROS生成及UCP2表达显著增加。42周时，OLETF大鼠冠状血管中的促纤维化生长因子转化生长因子（TGF）-β1、内皮型一氧化氮合酶和主动脉硝基酪氨酸增加。相反，主动脉中NO - cGMP途径的指标、磷酸化血管舒张刺激磷蛋白和超氧化物歧化酶活性显著降低。热量限制饮食的糖尿病大鼠心血管功能中UCP2与ROS生成之间的关系尚不清楚。CR使OLETF大鼠的这些异常恢复到正常水平。CR通过使OLETF大鼠的ROS生成正常化，显著改善了NO - cGMP途径。CR导致的UCP2表达降低可能是一种抵消细胞内氧化应激降低的代偿机制。数据表明，CR可能预防心血管组织受到糖尿病引发的氧化应激。
