Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats
Calorie restriction improves cardiovascular risk factors via reduction of mitochondrial reactive oxygen species in type II diabetic rats
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DOI：
10.1124/jpet.106.110460
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Okada, Shigeru
中科院分区：
文献类型：
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作者：
Minamiyama, Yukiko;Bito, Yasuyuki;Okada, Shigeru
解偶联蛋白2(UCP2)是细胞内活性氧(ROS)产生的重要调节因子。我们测定了热量限制(CR)对II型糖尿病大鼠心血管组织线粒体ROS生成、UCP2和一氧化氮(NO)-cGMP途径的动态影响。从29周龄到42周龄，一些大鼠接受限制饮食(自由摄入量减少30%)。29周时，OLETF组大鼠血糖、糖化血红蛋白、血浆游离脂肪酸、三酰甘油和纤溶酶原激活物抑制物-1水平显著高于非糖尿病对照组[Long-Evans Tokushima Otsuka(LETO)]大鼠。与LETO大鼠相比，OLETF大鼠心脏和主动脉线粒体ROS生成和UCP2表达均显著增加。42周时，OLETF大鼠冠状动脉中的纤维化生长因子、转化生长因子-β1、内皮型一氧化氮合酶和主动脉硝基酪氨酸均升高。相反，主动脉中NO-cGMP途径、磷酸化血管扩张剂刺激的磷蛋白和超氧化物歧化酶活性的指数显著降低。在糖尿病大鼠的心血管功能中，UCP2和ROS的产生之间的关系尚不清楚。OLETF大鼠的上述异常可被CR逆转至正常水平。CR通过使OLETF大鼠体内ROS生成正常化，显著改善NO-cGMP途径。CR降低UCP2的表达可能是抵消细胞内氧化应激降低的一种代偿机制。这些数据表明，CR可能预防糖尿病引起的心血管组织的氧化应激。
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.