TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis
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.
- SourceAvailable from: Xiaoqiang Tang
[Show abstract] [Hide abstract]
- "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). "
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.Frontiers in Physiology 05/2014; 5:175. DOI:10.3389/fphys.2014.00175 · 3.50 Impact Factor
[Show abstract] [Hide abstract]
- "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). "
ABSTRACT: Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPARγ) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI) and PPARγ in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals.Memórias do Instituto Oswaldo Cruz 09/2013; 108(6):741-54. DOI:10.1590/0074-0276108062013011 · 1.57 Impact Factor
[Show abstract] [Hide abstract]
- "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  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 , , , . In addition, SNAP and AICAR displayed a trend of increasing levels of TFAM and POLG suggesting increased mitochondrial biogenesis. "
ABSTRACT: Human embryonic stem cell (hESC) derivatives show promise as viable cell therapy options for multiple disorders in different tissues. Recent advances in stem cell biology have lead to the reliable production and detailed molecular characterisation of a range of cell-types. However, the role of mitochondria during differentiation has yet to be fully elucidated. Mitochondria mediate a cells response to altered energy requirements (e.g. cardiomyocyte contraction) and, as such, the mitochondrial phenotype is likely to change during the dynamic process of hESC differentiation. We demonstrate that manipulating mitochondrial biogenesis alters mesendoderm commitment. To investigate mitochondrial localisation during early lineage specification of hESCs we developed a mitochondrial reporter line, KMEL2, in which sequences encoding the green fluorescent protein (GFP) are targeted to the mitochondria. Differentiation of KMEL2 lines into the three germ layers showed that the mitochondria in these differentiated progeny are GFP positive. Therefore, KMEL2 hESCs facilitate the study of mitochondria in a range of cell types and, importantly, permit real-time analysis of mitochondria via the GFP tag.PLoS ONE 12/2012; 7(12):e52214. DOI:10.1371/journal.pone.0052214 · 3.23 Impact Factor