AMPKα1 regulates the antioxidant status of vascular endothelial cells

Abstract

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKalpha1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKalpha1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, gamma-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKalpha1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKalpha1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

“…AMPKa1 also regulates oxidative stress by controlling the expression of various genes involved in antioxidant defense such as manganese superoxide dismutase, g-glutamylcysteine synthase, and thioredoxin in endothelial cells (57). Oxidative stress upregulates the cascade of NF-kB, expression of cell adhesion molecules, and extravasations of mononuclear cells during EAE disease.…”

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…Studies have shown that AMPK signaling (likely via PGC1␣) stimulates the expression of anti-oxidant enzymes (61,62) whereas PI3K/Akt signaling impairs ROS scavenging (63,64). Consistently, we observed that blocking the AMPK pathway largely eliminated the apelin-stimulated expression of anti-oxidant enzymes (catalase, GPx) and apelin-suppressed expression of pro-oxidant enzyme (P47phox subunit of NADPH oxidase) and inhibiting PI3K/Akt led to up-regulation of antioxidant enzymes (SOD1 and catalase) (Fig.…”

The AMPK-FoxO3A axis as a target for cancer treatment

“…39 Moreover, recent evidences indicate the existence of an alternative pathway of AMPK activation, triggered by mitochondrial ROS and involving FoxO3A and its target genes (SOD, catalase, PGC1α). 40 Yet, several questions remain unanswered. Although it is largely accepted that activated AMPK is able to directly phosphorylate FoxO3A, the physiological or patho-physiological stimuli triggering AMPK-dependent FoxO3A phosphorylation still have to be identified and, most importantly, it is not clear yet which FoxO3A functions are actually regulated by these multiple phosphorylations.…”