TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis

Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 01/2009; 379(1):43-8. DOI: 10.1016/j.bbrc.2008.11.141
Source: PubMed


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.

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    • "Metformin, which activates AMPK, has been shown to inhibit mPTP opening and endothelial cell apoptosis and to prevent endothelial dysfunction in experimental models (Schulz et al., 2008) and to stimulate microvascular repair in acute lung injury (Jian et al., 2013). The thiazolidinediones, including pioglitazone, have been reported to activate PGC1-α, a downstream factor of AMPK and SIRT1, and enhance mitochondrial biogenesis in ECs (Fujisawa et al., 2009). Rapamycin, the inhibitor of mTOR, is evidenced to attenuate atherosclerosis (Waksman et al., 2003), hypertension and PAH (Morales et al., 2001; Nishimura et al., 2001). "
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    • "Central inflammatory pathways such as NF-κB, activator protein 1 and STAT have been found to be antagonised by PPARs in monocyte-macrophages, whereas down-regulation of these signalling pathways by thiazolidine-2-4-diones (TZDs), including pioglitazone (PGZ) and rosiglitazone (RGZ), has been shown to lead to reduced levels of oxidative products (Jiang et al. 1998). It has been found that TZDs were able to attenuate hyperglycaemia-induced ROS production by inducing manganese superoxide dismutase and promoting mitochondrial biogenesis (Fujisawa et al. 2009). Recently, PPARγ agonists have been suggested as a potential approach for down-regulating the inflammatory response to virus-induced inflammation (Bassaganya-Riera et al. 2010). "
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    • "SNAP is a nitric oxide (NO) donor, also known to increase expression of mitochondrial biogenesis genes such as TFAM and POLG however its mode of action is to directly activate PGC-1α [49] thus indirectly increasing mitochondrial biogenesis. The fold changes (1.5 to 3) we observed in the mitochondrial biogenesis regulators TFAM and POLG, although variable, concurred with published results [15], [21], [39], [50]. In addition, SNAP and AICAR displayed a trend of increasing levels of TFAM and POLG suggesting increased mitochondrial biogenesis. "
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