AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes

Abstract

Exposure of cardiomyocytes to high glucose concentrations (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase (NOX2). NOX2 activation is triggered by enhanced glucose transport through a sodium-glucose cotransporter (SGLT) but not by a stimulation of glucose metabolism. The aim of this work was to identify potential therapeutic approaches to counteract this glucotoxicity. In cultured adult rat cardiomyocytes incubated with 21 mM glucose (HG), AMP-activated protein kinase (AMPK) activation by A769662 or phenformin nearly suppressed ROS production. Interestingly, glucagon-like peptide 1 (GLP-1), a new antidiabetic drug, concomitantly induced AMPK activation and prevented the HG-mediated ROS production (maximal effect at 100 nM). α2-AMPK, the major isoform expressed in cardiomyocytes (but not α1-AMPK), was activated in response to GLP-1. Anti-ROS properties of AMPK activators were not related to changes in glucose uptake or glycolysis. Using in situ proximity ligation assay, we demonstrated that AMPK activation prevented the HG-induced p47phox translocation to caveolae, whatever the AMPK activators used. NOX2 activation by either α-methyl-d-glucopyranoside, a glucose analog transported through SGLT, or angiotensin II was also counteracted by GLP-1. The crucial role of AMPK in limiting HG-mediated NOX2 activation was demonstrated by overexpressing a constitutively active form of α2-AMPK using adenoviral infection. This overexpression prevented NOX2 activation in response to HG, whereas GLP-1 lost its protective action in α2-AMPK-deficient mouse cardiomyocytes. Under HG, the GLP-1/AMPK pathway inhibited PKC-β2 phosphorylation, a key element mediating p47phox translocation. In conclusion, GLP-1 induces α2-AMPK activation and blocks HG-induced p47phox translocation to the plasma membrane, thereby preventing glucotoxicity.

Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

“…Activation of classical PKCs was observed in skeletal muscles of obese humans and in high fat-fed murine hearts ( 51,52 ). Consistent with our fi ndings, activation of Nox2 by PKC ␤ II was also observed in CMs exposed to hyperglycemia ( 53 ). Although Nox2 activation by PKC contributes to oxidative stress, its role in autophagy mediated by lipid-induced oxidative stress is unknown.…”

Long Non-Coding RNA MALAT1 Protects Human Osteoblasts from Dexamethasone-Induced Injury via Activation of PPM1E-AMPK Signaling

“…AMPK activation can inhibit ROS production and oxidative injury [27,51]. AMPK activation is essential for NADPH homeostasis [27,51].…”

“…AMPK activation is essential for NADPH homeostasis [27,51]. Activated AMPK phosphorylates ACC to prevent NADPH consumption [27].…”

“…Studies have shown that AMPK activation can inhibit Dex-induced ROS production [4,30,31,49,50]. Activated AMPK can increase NADPH content and activity to attenuate oxidative stress [49,51]. AMPK can also induce activation of Nrf2 signaling [28][29][30], which is a key cellular defense mechanism against oxidative stress [52][53][54].…”

Suppressive Effects of Glucose-Dependent Insulinotropic Polypeptide on Cardiac Hypertrophy and Fibrosis in Angiotensin II-Infused Mouse Models

“…25 There is a study reporting that the activation of GLP-1R, which shares a number of similarities with GIPR, prevents NADPH oxidase activation induced by hyperglycemia in mouse cardiomyocytes. 26 It is also reported that GIP suppressed p38 MAPK in rat islet β cells. 27 Although differences in receptor and cell types need to be considered, the suppression of NADPH oxidase and/or p38 MAPK activity might be a possible mechanism in the suppression of TGF-β1 expression by GIP signaling.…”