Article

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: 2.28). 01/2009; 379(1):43-8. DOI: 10.1016/j.bbrc.2008.11.141
Source: PubMed

ABSTRACT 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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    Frontiers in Physiology 05/2014; 5:175. DOI:10.3389/fphys.2014.00175 · 3.50 Impact Factor
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    • "The hypothesis that mitochondrial biogenesis might be a cell response contributing to the cytoprotective effects of PPAR agonists is also indicated by previous results. Thus, thiazolidinedione-induced mitochondrial biogenesis sustains cell survival of normal and malignant T cells (Jo et al., 2006; Yang et al., 2007a), preserves the integrity of human umbilical vein endothelial cells (Fujisawa et al., 2009) and could contribute to the neuroprotection exerted by pioglitazone and rosiglitazone (Strum et al., 2007; Miglio et al., 2009; Semple and Noble-Haeusslein, 2011). Interestingly, mitochondrial biogenesis has been proposed to mediate (at least in part) the protective effects exerted by different agents shared by the ability to induce PGC-1a expression. "
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