Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells

Ouslimani, Nadjat; Peynet, Jacqueline; Bonnefont‐Rousselot, Dominique; Thérond, Patrice; Legrand, Alain; Beaudeux, Jean-Louis

doi:10.1016/j.metabol.2005.01.029

Cited by 183 publications

(125 citation statements)

References 51 publications

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“…Our observations are in line with previous studies reporting that AMPK activation improves vascular endothelial functions 15 and mitigates ER stress 9 and reactive oxygen species (ROS) production 16 associated with diabetes mellitus. Furthermore, PPARδ is known to regulate cardiovascular function: its activation induces angiogenesis and vasculogenesis, inhibits atherosclerosis, and protects endothelial function in diabetic mice.…”

Section: Discussionsupporting

confidence: 93%

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Cheang

Tian

Wong

et al. 2014

ATVB

167

114

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Objective— 5′ Adenosine monophosphate–activated protein kinase (AMPK) interacts with peroxisome proliferator–activated receptor δ (PPARδ) to induce gene expression synergistically, whereas the activation of AMPK inhibits endoplasmic reticulum (ER) stress. Whether the vascular benefits of antidiabetic drug metformin (AMPK activator) in diabetes mellitus and obesity is mediated by PPARδ remains unknown. We aim to investigate whether PPARδ is crucial for metformin in ameliorating ER stress and endothelial dysfunction induced by high-fat diet. Approach and Results— Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph. ER stress markers were determined by Western blotting. Superoxide production in mouse aortae and NO generation in mouse aortic endothelial cells were assessed by fluorescence imaging. Endothelium-dependent relaxation was impaired and ER stress markers and superoxide level were elevated in aortae from high-fat diet–induced obese mice compared with lean mice. These effects of high-fat diet were reversed by oral treatment with metformin in diet-induced obese PPARδ wild-type mice but not in diet-induced obese PPARδ knockout littermates. Metformin and PPARδ agonist GW1516 reversed tunicamycin (ER stress inducer)-induced ER stress, oxidative stress, and impairment of endothelium-dependent relaxation in mouse aortae as well as NO production in mouse aortic endothelial cells. Effects of metformin were abolished by cotreatment of GSK0660 (PPARδ antagonist), whereas effects of GW1516 were unaffected by compound C (AMPK inhibitor). Conclusions— Metformin restores endothelial function through inhibiting ER stress and oxidative stress and increasing NO bioavailability on activation of AMPK/PPARδ pathway in obese diabetic mice.

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Section: Discussionsupporting

confidence: 93%

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Cheang

Tian

Wong

et al. 2014

ATVB

167

114

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“…It has been previously shown that several tissues endangered by oxidative imbalance associated with T2D, particularly the myocardium (38,44), endothelial cells (5,48), and the brain (13), could be protected by metformin administration. Surprisingly, there are scarce data regarding the antioxidant effect of metformin in the fatty liver, despite the fact that steatosis is a hallmark of T2D and that the fatty liver is highly susceptible to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

Cahová

Páleníčková

Daňková

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Z, Oliyarnyk O, Kazdova L. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309: G100 -G111, 2015. First published June 4, 2015; doi:10.1152/ajpgi.00329.2014.-Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt Ϫ1 ·day Ϫ1 ). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH-and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-␣, TLR4, IL-1␤, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation. metformin; oxidative stress; mitochondrial respiration; liver injury; 31 P MR spectroscopy METFORMIN IS AN ORAL ANTIHYPERGLYCEMIC drug widely used in the treatment of Type 2 diabetes (T2D) (7). There is evidence that metformin also protects against oxidative stress in various tissues, although the antioxidant activity of metformin is not well understood. It has been shown that hyperglycemia is associated with increased reactive oxygen species (ROS) formation due to superoxide overproduction from the mitochondrial electron transport chain as a consequence of increased glycolysis (8). It has been hypothesized that the antioxidative effect of metformin is simply the consequence of its glucoselowering effect and subsequent decrease in superoxide anion production (3). Nevertheless, metformin has also displayed antioxidative characteristics in several models of oxidative stress without hyperglycemia (2,19,20,2...

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Section: Positive Effectsmentioning

confidence: 99%

“…Similar findings of enhancing the antioxidant function were observed when using diet-induced obesity rats (i.e., higher superoxide dismutase and glutathione peroxidase, and lower malondialdehyde) (Fang et al, 2012). In fact, metformin was identified as having antioxidant activity against oxidative damage by reactive oxygen species (Cahova et al., 2015;Ouslimani et al, 2005).Moreover, metformin was found to enhance the phosphorylation of 5'-AMP activated protein kinase (AMPK), which is a sensor protein of cellular energy status, thus, a strategic enzyme in regulating energy balances (i.e., glucose and lipid metabolism) (Bertoldo et al, 2015;Hardie et al, 2003;Ma et al, 2015;Nguyen et al, 2014Nguyen et al, , 2015. Therefore, metformin may improve sperm function via enhancing the activity of AMPK.…”

mentioning

confidence: 99%

Effect of metformin on semen quality

Banihani

2016

Braz. J. Pharm. Sci.

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Various studies have linked metformin, a universally antidiabetic drug, with semen quality; however, such a direct link has not been established. This review systematically addresses and summarizes the effect of metformin on semen quality, particularly sperm function. We searched the MEDLINE electronic database for English articles and abstracts containing the key words 'metformin' and 'sperm', and relevant articles were reviewed. In summary, metformin appears to have improved and provided positive impact on sperm quality. This effect may be due to the ability of metformin to reduce oxidative stress and lipid peroxidation, enhance 5'-AMP activated protein kinase activity, and restore the normal levels of pituitary-gonadal hormones. However, further clinical research is still necessary to confirm such effect.Uniterms: Metformin/effects. Metformin/review. Metformin/semen quality. Sperm/study. Testosterone. Oxidative stress. 5'-AMP activated protein kinase. INTRODUCTIONMetformin, a biguanide-derivative antidiabetic drug, is the most widely used oral agent in humans (Brinkmann, Brixius, 2015;Chhetri, Thapa, Van Schepdael, 2014). It is the first-line drug for the treatment of type 2 diabetes, particularly, in overweight and obese patients with normal kidney function (American Diabetes, 2009;George, Joseph, 2014;Hung et al., 2015). In addition, recent research has proposed that metformin alone or in combination with insulin may be safe to treat gestational diabetes and does not increase the risk of metabolic acidosis (Huang, Castelino, Peterson, 2015; Kitwitee et al., 2015). Metformin's mechanism of action involves suppression of hepatic gluconeogenesis (Ferrannini, 2014; Foretz et al., 2010;Todd, Florez, 2014). One concern that has been raised relevant to metformin usage is that the consensus panel of diabetes felt that metformin should be considered for diabetes prevention even in non-diabetic individuals (i.e., pre-diabetic or obese individuals). This concern increases the use of this drug by these groups (American Diabetes, 2009;Hostalek, Gwilt, Hildemann, 2015;Manu et al., 2015;McGavock, Dart, Wicklow, 2015).Over the last decade, various experimental and clinical studies have linked metformin with sperm function, and thus with male factor infertility Ferreira et al., 2015); however, such direct link has not been established. In this review, we provide fresh and comprehensive understanding of the effect of metformin, as a universally used oral agent, on semen quality (i.e., sperm quantity and quality). To do this, we searched the MEDLINE electronic database for English-language articles and abstracts reported using the key words 'metformin' and 'sperm'. The references from selected articles were reviewed and used if relevant. Effect of metformin on sperm parameters Positive effectsTo date, the majority of studies linking metformin to sperm parameters are nonclinical. In his study on streptozotocin-induced diabetic rats, Attia, Helal, Alhaider (2009) made the seminal observation that metformin decreases the diabe...

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Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells

Cited by 183 publications

References 51 publications

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5′ Adenosine Monophosphate–Activated Protein Kinase–Peroxisome Proliferator–Activated Receptor δ Pathway

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

Effect of metformin on semen quality

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