TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis.
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.
Fujisawa
Kazuo
K
Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Nishikawa
Takeshi
T
Kukidome
Daisuke
D
Imoto
Koujirou
K
Yamashiro
Takeshi
T
Motoshima
Hiroyuki
H
Matsumura
Takeshi
T
Araki
Eiichi
E
D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000032:analysis / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077205:Pioglitazone; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D014470:Umbilical Cord / Q000166:cytology
D004272:DNA, Mitochondrial; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D014157:Transcription Factors; D013482:Superoxide Dismutase; C039671:ciglitazone; D000077205:Pioglitazone