Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat.
Saxagliptin restores vascular mitochondrial exercise response in the Goto-Kakizaki rat.
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DOI：
10.1097/fjc.0000000000000170
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发表时间：
2015-02
影响因子：
3
通讯作者：
Reusch JE
中科院分区：
文献类型：
--
作者：
Keller AC;Knaub LA;Miller MW;Birdsey N;Klemm DJ;Reusch JE
心血管疾病风险和全因死亡率很大程度上是通过身体健康来预测的。运动通过内皮一氧化氮合酶 (eNOS)、sirtuins 和 PPARγ 共激活剂 1α (PGC-1α) 刺激血管线粒体生物发生，而糖尿病和高血压中不存在这种反应。我们假设在糖尿病背景下调节 eNOS 的药物可以重建运动介导的线粒体生物发生信号。胰高血糖素样肽 1 (GLP-1) 刺激 eNOS 和血流；我们使用沙格列汀（一种 GLP-1 降解抑制剂）来测试糖尿病患者血管线粒体对运动的适应是否可以恢复。 Goto-Kakizaki (GK) 大鼠（一种非肥胖 2 型糖尿病模型）和 Wistar 对照组接受为期 8 天的运动干预，有或没有沙格列汀（10 mg·kg−1·d−1）。我们评估了运动和沙格列汀对主动脉线粒体蛋白和信号通路的影响。 Wistar 主动脉中线粒体蛋白表达随着运动而增加，而 GK 动物中线粒体蛋白表达降低或保持不变。用沙格列汀加运动治疗的 GK 大鼠显示线粒体复合物、细胞色素 c、eNOS、nNOS、PGC-1α 和 UCP3 蛋白的表达增加。值得注意的是，为期 3 周的沙格列汀加运动干预显着增加了 GK 大鼠的跑步时间。这些数据表明，沙格列汀可以恢复糖尿病啮齿动物模型中血管线粒体对运动的适应，并可能增强运动对脉管系统的影响。
Cardiovascular disease risk and all-cause mortality are largely predicted by physical fitness. Exercise stimulates vascular mitochondrial biogenesis through endothelial nitric oxide synthase (eNOS), sirtuins, and PPARγ coactivator 1α (PGC-1α), a response absent in diabetes and hypertension. We hypothesized that an agent regulating eNOS in the context of diabetes could reconstitute exercise-mediated signaling to mitochondrial biogenesis. Glucagon-like peptide 1 (GLP-1) stimulates eNOS and blood flow; we used saxagliptin, an inhibitor of GLP-1 degradation, to test whether vascular mitochondrial adaptation to exercise in diabetes could be restored. Goto-Kakizaki (GK) rats, a nonobese, type 2 diabetes model, and Wistar controls were exposed to an 8-day exercise intervention with or without saxagliptin (10 mg·kg−1·d−1). We evaluated the impact of exercise and saxagliptin on mitochondrial proteins and signaling pathways in aorta. Mitochondrial protein expression increased with exercise in the Wistar aorta and decreased or remained unchanged in the GK animals. GK rats treated with saxagliptin plus exercise showed increased expression of mitochondrial complexes, cytochrome c, eNOS, nNOS, PGC-1α, and UCP3 proteins. Notably, a 3-week saxagliptin plus exercise intervention significantly increased running time in the GK rats. These data suggest that saxagliptin restores vascular mitochondrial adaptation to exercise in a diabetic rodent model and may augment the impact of exercise on the vasculature.