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Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages.

Bułdak Ł, Łabuzek K, Bułdak RJ, Machnik G, Bołdys A, Okopień B - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

Bottom Line: According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px.We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89.This effect relied on the stimulation of GLP-1 receptor.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Medykow 18, 40-752, Katowice, Poland, lbuldak@gmail.com.

ABSTRACT
Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.

No MeSH data available.


Related in: MedlinePlus

The influence of protein kinase A inhibitor (H89) on the activities of a superoxide dismutase, b glutathione peroxidase, and c catalase in monocytes/macrophages treated with exenatide. *p < 0.05, **p < 0.01, ***p < 0.001
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Fig7: The influence of protein kinase A inhibitor (H89) on the activities of a superoxide dismutase, b glutathione peroxidase, and c catalase in monocytes/macrophages treated with exenatide. *p < 0.05, **p < 0.01, ***p < 0.001

Mentions: Exenatide considerably elevated CAT mRNA and protein level by 75 and 22 %, but it did not change the activity of the enzyme. LPS did not affect the expression and activity of CAT. Compared to control, an increase in mRNA level was observed in cultures with LPS plus exenatide (by 44 %); however, this rise was smaller than that observed in cells only treated with exenatide (by 18 %). In the group treated with LPS plus exenatide, a modest elevation in CAT activity was observed (by 14 %) despite the lack of an influence on protein expression. Exendin 9-39 did not affect the enzymatic activity of CAT compared to LPS and exenatide. Exendin 9-39 did not reverse the exenatide-induced increase of enzymatic activity of CAT in the presence of LPS suggesting GLP-1 receptor independent effects (Sathananthan et al. 2013). These results are somewhat puzzling, but overall, it seems reasonable to assume that the influence of exenatide on catalase activity is at best modest and shows increasing activity with the simultaneous inflammatory stimulus.


Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages.

Bułdak Ł, Łabuzek K, Bułdak RJ, Machnik G, Bołdys A, Okopień B - Naunyn Schmiedebergs Arch. Pharmacol. (2015)

The influence of protein kinase A inhibitor (H89) on the activities of a superoxide dismutase, b glutathione peroxidase, and c catalase in monocytes/macrophages treated with exenatide. *p < 0.05, **p < 0.01, ***p < 0.001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537507&req=5

Fig7: The influence of protein kinase A inhibitor (H89) on the activities of a superoxide dismutase, b glutathione peroxidase, and c catalase in monocytes/macrophages treated with exenatide. *p < 0.05, **p < 0.01, ***p < 0.001
Mentions: Exenatide considerably elevated CAT mRNA and protein level by 75 and 22 %, but it did not change the activity of the enzyme. LPS did not affect the expression and activity of CAT. Compared to control, an increase in mRNA level was observed in cultures with LPS plus exenatide (by 44 %); however, this rise was smaller than that observed in cells only treated with exenatide (by 18 %). In the group treated with LPS plus exenatide, a modest elevation in CAT activity was observed (by 14 %) despite the lack of an influence on protein expression. Exendin 9-39 did not affect the enzymatic activity of CAT compared to LPS and exenatide. Exendin 9-39 did not reverse the exenatide-induced increase of enzymatic activity of CAT in the presence of LPS suggesting GLP-1 receptor independent effects (Sathananthan et al. 2013). These results are somewhat puzzling, but overall, it seems reasonable to assume that the influence of exenatide on catalase activity is at best modest and shows increasing activity with the simultaneous inflammatory stimulus.

Bottom Line: According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px.We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89.This effect relied on the stimulation of GLP-1 receptor.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia, Medykow 18, 40-752, Katowice, Poland, lbuldak@gmail.com.

ABSTRACT
Macrophages are dominant cells in the pathogenesis of atherosclerosis. They are also a major source of reactive oxygen species (ROS). Oxidative stress, which is particularly high in subjects with diabetes, is responsible for accelerated atherosclerosis. Novel antidiabetic drugs (e.g., glucagon-like peptide-1 (GLP-1) agonists) were shown to reduce ROS level. Therefore, we conceived a study to evaluate the influence of exenatide, a GLP-1 agonist, on redox status in human monocytes/macrophages cultured in vitro, which may explain the beneficial effects of incretin-based antidiabetic treatment. Human macrophages obtained from 10 healthy volunteers were in vitro subjected to the treatment with GLP-1 agonist (exenatide) in the presence of lipopolysaccharide (LPS), antagonist of GLP-1 receptors (exendin 9-39), or protein kinase A inhibitor (H89). Afterwards, reactive oxygen species, malondialdehyde level, NADPH oxidase, and antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase] expression was evaluated. Finally, we estimated the activity of the abovementioned enzymes in the presence of H89. According to our findings, exenatide reduced ROS and malondialdyhyde (MDA) level by decreasing the expression of ROS-generating NADPH oxidase and by increasing the expression and activities of SOD and GSH-Px. We also showed that this effect was significantly inhibited by exendin 9-39 (a GLP-1 antagonist) and blocked by H89. Exenatide improved the antioxidative potential and reduced oxidative stress in cultured human monocytes/macrophages, and this finding may be responsible for the pleiotropic effects of incretin-based therapies. This effect relied on the stimulation of GLP-1 receptor.

No MeSH data available.


Related in: MedlinePlus