Activation of AMP-activated Protein Kinase by Vascular Endothelial Growth Factor Mediates Endothelial Angiogenesis Independently of Nitric-oxide Synthase

Stahmann, Nadine; Woods, Angela; Spengler, Katrin; Heslegrave, Amanda; Bauer, Reinhard; Krause, S.; Viollet, Benoı̂t; Carling, David; Heller, Regine

doi:10.1074/jbc.m110.108688

Cited by 84 publications

(86 citation statements)

References 86 publications

(105 reference statements)

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“…Alternatively, the kinetics of AMPK activation may dictate the nature of the proliferative response. In particular, chronic, sustained activation of AMPK that was observed in our study may favor endothelial cell growth arrest, whereas acute, transient activation of AMPK in response to angiogenic factors promotes a proliferative response (Ouchi et al, 2004;Stahmann et al, 2010;Su et al, 2012). The ability of AMPK to repress endothelial cell growth, an ATP-consuming process, provides another mechanism by which this kinase conserves energy during periods of prolonged metabolic stress.…”

Section: Discussionmentioning

confidence: 54%

Activation of AMP-Activated Protein Kinase Inhibits the Proliferation of Human Endothelial Cells

Peyton

Liu

Yan

et al. 2012

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 54%

Activation of AMP-Activated Protein Kinase Inhibits the Proliferation of Human Endothelial Cells

Peyton

Liu

Yan

et al. 2012

J Pharmacol Exp Ther

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“…Although we did not directly assess cardiac function, in contrast to LKB1 MCK-Cre mice (42, 43), we did not detect any change in heart size suggesting that heart function was not adversely affected. Reductions in blood flow may also be related to reduced skeletal muscle capillarization, which has been observed in AMPK α2 KD mice (44)(45)(46). In addition to regulating angiogenesis, skeletal muscle AMPK is also important for regulating nitric oxide synthase (NOS), which is important for controlling blood flow and glucose delivery during exercise (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

“…Reductions in blood flow may also be related to reduced skeletal muscle capillarization, which has been observed in AMPK α2 KD mice (44)(45)(46). In addition to regulating angiogenesis, skeletal muscle AMPK is also important for regulating nitric oxide synthase (NOS), which is important for controlling blood flow and glucose delivery during exercise (44)(45)(46). Future studies examining heart function, muscle capillary density, and glucose delivery/blood flow in β1β2M-KO mice are warranted.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

O’Neill

Maarbjerg

Crane

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

366

388

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AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate. However, compensatory up-regulation and redundancy of AMPK subunits in wholebody AMPK α2, β2, and γ3 null mice has made it difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice with single mutations or deletions in muscle α, β, or γ subunits.is an evolutionarily conserved stress-sensing kinase that controls energy metabolism and appetite by responding to nutrients and hormones (1). The regulation of AMPK activity depends on AMP and ADP regulated phosphorylation of the α catalytic subunit at T172 by the upstream kinases LKB1 and Ca 2+ /CaM-dependent protein kinase kinase (CaMKKβ; refs. 2 and 3). AMPK exists as a heterotrimer, consisting of an α catalytic subunit (α1, α2), a scaffolding β subunit (β1, β2) and a nucleotide-binding γ subunit (γ1, γ2, γ3) (1). The C-terminal of the β subunit contains a highly conserved α and γ subunit-binding sequence (SBS) that is required for the formation of a stable, active AMPK αβγ complex (4). We recently reported on the physiological effects of germline deletion of β1 (5) and β2 (6) isoforms in mice. We showed that β1 null mice have reduced AMPK α-subunit expression and activity in liver, adipose tissue and the hypothalamus (5). In contrast, AMPK β2 null mice have reduced AMPK activity in skeletal muscle, are aminoimidazole carboxamide ribonucleotide (AICAR) insensitive and have reduced exercise tolerance despite a greater than 50% increase in muscle β1 protein expression (6). The phenotype of β2 null mice was similar to that of mice lacking α2 (7) or γ3 (8) subunits or muscle-specific overexpression of an α2 kinase dead (KD) mutation (9, 10).During exercise, AMPK is activated in an intensity-dependent manner (for review, see ref. 11). Mice with reduced AMPK in muscle are exercise intolerant, an effect shown not to be due to cardiac impairments in AMPK (12-14). However, the cause for this reduction in exercise capacity remains largely unknown, because mitochondrial content and glucose uptake are not altered (6,7,10,12,(15)(16)(17) or onl...

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“…Thus, there may be some flexibility in the spacing between this motif and the phosphoamino acid. However, it is worth noting that another site that has a sequence motif similar to that on PFKFB2 (i.e., Ser 1177 on endothelial nitric oxide synthase [eNOS]), while apparently phosphorylated by AMPK in cell-free assays (Chen et al 1999), does not appear to be a target in intact cells (Stahmann et al 2006(Stahmann et al , 2010. There are also a few proteins that have been claimed to be direct substrates for AMPK that are even poorer fits to this consensus, including eukaryotic elongation factor-2 (eEF2) kinase (Browne et al 2004), p53 (Jones et al 2005), and p27…”

Section: Recognition Of Substratesmentioning

confidence: 99%

AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

Hardie¹

2011

Genes Dev.

1,343

1,179

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AMP-activated protein kinase (AMPK) is a sensor of energy status that maintains cellular energy homeostasis. It arose very early during eukaryotic evolution, and its ancestral role may have been in the response to starvation. Recent work shows that the kinase is activated by increases not only in AMP, but also in ADP. Although best known for its effects on metabolism, AMPK has many other functions, including regulation of mitochondrial biogenesis and disposal, autophagy, cell polarity, and cell growth and proliferation. Both tumor cells and viruses establish mechanisms to down-regulate AMPK, allowing them to escape its restraining influences on growth.Living cells use ATP and ADP in a manner similar to the chemicals in a rechargeable battery. Most cellular processes require energy and are driven (directly or indirectly) by the hydrolysis of ATP to ADP and phosphate (or, less frequently, to AMP and pyrophosphate), thus ''flattening the battery.'' In heterotrophic organisms, the battery is recharged by catabolism; i.e., the oxidation of reduced carbon compounds of organic origin, such as glucose. In most cells (especially quiescent cells), oxidation of glucose usually proceeds completely to carbon dioxide via the process of oxidative phosphorylation. Under these conditions, most ATP synthesis occurs at the inner mitochondrial membrane, ATP being generated when protons pumped out via the respiratory chain flow back across the membrane via channels in complex V (the ATP synthase). It has been argued that the endosymbiotic acquisition of aerobic bacteria to form mitochondria was the crucial event in the development of the eukaryotes (Lane and Martin 2010). The large increase in surface area of membrane available for proton transfer (in the form of the inner mitochondrial membrane) allowed a large increase in capacity to generate ATP, which may in turn have allowed the dramatic increase in complexity displayed by eukaryotic cells and organisms. When mitochondria became the main cellular power source, one additional event required was the development of systems that sense energy status in the cytoplasm and then signal this information back to modulate mitochondrial function. Interestingly, AMP-activated protein kinase (AMPK, the subject of this review) fulfills this role and appears to be almost universal in eukaryotes. One interesting exception is Encephalitozoon cuniculi, a eukaryote with a strippeddown genome that appears to have lost not only its mitochondria, but also AMPK (Miranda-Saavedra et al. 2007). However, as it is an obligate intracellular parasite, the host cell would provide both of these missing functions.The obvious way to achieve energy sensing would be to have proteins that monitor the cellular ratio of ATP:ADP. However, because of the very active adenylate kinases in all eukaryotic cells, which catalyze the interconversion of adenine nucleotides (2ADP 4 ATP + AMP), the AMP:ATP ratio tends to change in concert with, and to an even greater extent than, the ADP:ATP ratio (Hardie and Hawley 2001). Thus,...

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Activation of AMP-activated Protein Kinase by Vascular Endothelial Growth Factor Mediates Endothelial Angiogenesis Independently of Nitric-oxide Synthase

Cited by 84 publications

References 86 publications

Activation of AMP-Activated Protein Kinase Inhibits the Proliferation of Human Endothelial Cells

Activation of AMP-Activated Protein Kinase Inhibits the Proliferation of Human Endothelial Cells

AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise

AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function

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