Abstract
Objective:
Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells.
Methods and results:
In Zucker diabetic fatty rats, a significant 2-fold higher level of vascular senescence was observed compared with control lean rats. Dipeptidyl-peptidase 4 (DPP-4) inhibition significantly increased GLP-1 levels in these animals and reduced senescence almost to lean animal levels. In vitro studies with human umbilical vein endothelial cells showed that GLP-1 had a direct protective effect on oxidative stress (H(2)O(2))-induced senescence and was able to attenuate oxidative stress-induced DNA damage and cellular senescence. The GLP-1 analogue exendin-4 provided similar results, whereas exendin fragment 9-39, a GLP-1 receptor antagonist, abolished this effect. Intracellular signaling by the phosphoinositide 3-kinase (PI3K)/Akt survival pathway did not appear to be involved. Further analysis revealed that GLP-1 activates the cAMP response element-binding (CREB) transcription factor in a cAMP/protein kinase A (PKA)-dependent manner, and inhibition of the cAMP/PKA pathway abolished the GLP-1 protective effect. Expression analysis revealed that GLP-1 can induce the oxidative defense genes HO-1 and NQO1.
Conclusions:
Dipeptidyl-peptidase 4 inhibition protects against vascular senescence in a diabetic rat model. In vitro studies with human umbilical vein endothelial cells showed that reactive oxygen species-induced senescence was attenuated by GLP-1 in a receptor-dependent manner involving downstream PKA signaling and induction of antioxidant genes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adamantane / analogs & derivatives
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Adamantane / pharmacology
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Animals
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Cells, Cultured
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Cellular Senescence* / drug effects
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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DNA Damage
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Diabetes Mellitus / drug therapy
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Diabetes Mellitus / enzymology*
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Diabetes Mellitus / pathology
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology*
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Endothelial Cells / pathology
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Enzyme Activation
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Exenatide
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Glucagon-Like Peptide 1 / metabolism*
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Glucagon-Like Peptide-1 Receptor
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Heme Oxygenase-1 / metabolism
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Humans
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Hydrogen Peroxide / pharmacology
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Hypoglycemic Agents / pharmacology
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Male
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NAD(P)H Dehydrogenase (Quinone) / metabolism
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Nitriles / pharmacology
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Oxidants / pharmacology
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Oxidative Stress* / drug effects
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Peptides / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrrolidines / pharmacology
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Rats
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Rats, Zucker
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Reactive Oxygen Species / metabolism*
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Receptors, Glucagon / metabolism
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Signal Transduction
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Venoms / pharmacology
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Vildagliptin
Substances
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Dipeptidyl-Peptidase IV Inhibitors
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GLP1R protein, human
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Glp1r protein, rat
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Glucagon-Like Peptide-1 Receptor
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Hypoglycemic Agents
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Nitriles
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Oxidants
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Peptides
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Pyrrolidines
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Reactive Oxygen Species
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Receptors, Glucagon
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Venoms
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Glucagon-Like Peptide 1
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Exenatide
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Hydrogen Peroxide
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Cyclic AMP
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HMOX1 protein, human
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Heme Oxygenase-1
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NAD(P)H Dehydrogenase (Quinone)
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NQO1 protein, human
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Cyclic AMP-Dependent Protein Kinases
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Vildagliptin
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Adamantane