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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    • "This inhibition of MSNA cannot be explained by a reduction in insulin resistance. Previous reports have shown that pioglitazone also reduces reactive oxygen species (Fujisawa et al., 2009), stimulating central sympathetic nerve activity accompanied by angiotensin II (Gao et al., 2004). We did not examine the relationship between reactive oxygen species and sympathetic excitation. "

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    • " ) , which has been implicated in Hunting - ton ' s disease , Parkinson ' s diseases , ALS , and other neurodegen - erative diseases ( Róna - Vörös and Weydt , 2010 ) . PPARγ agonists thiazolidinediones ( TZDs ) were shown to reduce hyperglycemia - induced ROS production and promoted mitochondria biogene - sis through activating PGC - 1α pathway ( Fujisawa et al . , 2009 ) . Although the death of motor neurons is the most prominent characteristics of ALS , the cytotoxicity of SOD1 ( G93A ) caused skeletal muscle atrophy might be an intrinsic characteristics of ALS pathogenesis ( Dobrowolny et al . , 2008 ) . This study aimed to investigate the effect of manipulating PGC - 1α pathway ( activat - ing PGC "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease causing death of motor neurons. This study investigated the roles of energy metabolism in the pathogenesis of ALS in the SOD1(G93A) transgenic mouse model. Control and SOD1(G93A) mice were administered with shcontrol or shPGC-1α in combination with PBS or thiazolidinedione (TZD) for 8 weeks. Gene expression was analyzed by quantitative real-time PCR and Western blot. ROS and fibrosis were assessed with a colorimetric kit and Sirius staining, respectively. Inflammatory cytokines were measured using ELISA kits. The levels of tissue ROS and serum inflammatory cytokines were significantly higher in SOD1(G93A) mice compared to control mice, and knocking down peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) drastically increased cytokine levels in both control and SOD1(G93A) mice. Muscle fibrosis was much severer in SOD1(G93A) mice, and worsened by silencing PGC-1α and attenuated by TZD. The expression levels of PGC-1α, SOD1, UCP2, and cytochrome C were substantially reduced by shPGC-1α and increased by TZD in muscle of both control and SOD1(G93A) mice, whereas the level of NF-κB was significantly elevated in SOD1(G93A) mice, which was further increased by PGC-1α silencing. These data indicated that disruption of energy homeostasis would exacerbate the pathological changes caused by SOD1 mutations to promote the pathogenesis of ALS.
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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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    ABSTRACT: Mitochondria are perhaps the most sophisticated and dynamic responsive sensing systems in eukaryotic cells. The role of mitochondria goes beyond their capacity to create molecular fuel and includes the generation of reactive oxygen species, the regulation of calcium, and the activation of cell death. In endothelial cells, mitochondria have a profound impact on cellular function under both healthy and diseased conditions. In this review, we summarize the basic functions of mitochondria in endothelial cells and discuss the roles of mitochondria in endothelial dysfunction and vascular diseases, including atherosclerosis, diabetic vascular dysfunction, pulmonary artery hypertension, and hypertension. Finally, the potential therapeutic strategies to improve mitochondrial function in endothelial cells and vascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants and calorie restriction.
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