Fujisawa Kazuo, Nishikawa Takeshi, Kukidome Daisuke, Imoto Koujirou, Yamashiro Takeshi, Motoshima Hiroyuki, Matsumura Takeshi, Araki Eiichi
Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Biochem Biophys Res Commun. 2009 Jan 30;379(1):43-8. doi: 10.1016/j.bbrc.2008.11.141. Epub 2008 Dec 11.
Although it has been reported that thiazolidinediones (TZDs) may reduce cardiovascular events in type 2 diabetic patients, its precise mechanism is unclear. We previously demonstrated that hyperglycemia-induced production of reactive oxygen species from mitochondria (mtROS) contributed to the development of diabetic complications, and metformin normalized mt ROS production by induction of MnSOD and promotion of mitochondrial biogenesis by activating the PGC-1alpha pathway. In this study, we examined whether TZDs could inhibit hyperglycemia-induced mtROS production by activating the PGC-1alpha pathway. We revealed that pioglitazone and ciglitazone attenuated hyperglycemia-induced ROS production in human umbilical vein endothelial cells (HUVECs). Both TZDs increased the expression of NRF-1, TFAM and MnSOD mRNA. Moreover, pioglitazone increased mtDNA and mitochondrial density. These results suggest that TZDs normalize hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis by activating PGC-1alpha. This phenomenon could contribute to the prevention of diabetic vascular complications.
尽管有报道称噻唑烷二酮类药物（TZDs）可能会降低2型糖尿病患者的心血管事件，但确切机制尚不清楚。我们之前证明，高血糖诱导的线粒体活性氧（mtROS）生成促成了糖尿病并发症的发展，而二甲双胍通过诱导锰超氧化物歧化酶（MnSOD）以及激活PGC-1α途径促进线粒体生物合成来使mtROS生成正常化。在本研究中，我们检测了TZDs是否能够通过激活PGC-1α途径来抑制高血糖诱导的mtROS生成。我们发现吡格列酮和环格列酮可减轻人脐静脉内皮细胞（HUVECs）中高血糖诱导的ROS生成。两种TZDs均增加了NRF-1、线粒体转录因子A（TFAM）和MnSOD mRNA的表达。此外，吡格列酮增加了线粒体DNA和线粒体密度。这些结果表明，TZDs通过诱导MnSOD以及激活PGC-1α促进线粒体生物合成来使高血糖诱导的mtROS生成正常化。这一现象可能有助于预防糖尿病血管并发症。
