Associate Editor: R.M. WadsworthAMPK and vasculoprotection
Introduction
AMP-activated protein kinase (AMPK) is a highly conserved, multi-substrate serine/threonine protein kinase involved in the regulation of cellular and whole organ metabolism. While the term AMPK was first coined by Sim and Hardie (1988) after its allosteric activator, AMP, historically the discovery of the enzyme dates back much further and was a consequence of studies by several laboratories. A protein kinase for HMG-CoA reductase was first identified by Beg et al. (1979), while a later publication (Ferrer et al., 1985) suggested this kinase was activated by AMP. Parallel studies by Lent and Kim (1982) discovered an acetyl-CoA-carboxylase kinase with related properties (reviewed in Hardie et al., 1998), and Carling et al. (2007) concluded that the acetyl-CoA-carboxylase kinase and HMG-CoA-reductase kinase were one and the same. When nutrient supply is limited, ATP generation impaired or cellular demand increased, AMPK is phosphorylated and this leads to the activation of ATP generating catabolic pathways and the down regulation of ATP consuming anabolic pathways (Hardie & Carling, 1997). Activation of the AMPK cascade, therefore, ultimately contributes to the maintenance of energy stores and justifies the status of AMPK as a cellular “fuel gauge” (Hardie & Carling, 1997).
Section snippets
5′ Adenosine monophosphate activated protein kinase structure
AMPK exists in heterotrimeric complexes comprising α, β and γ subunits, each having two or more isoforms (α1, α2, β1, β2, γ1, γ2, and γ3) which are differentially expressed in various tissues and sub-cellular locations. Each isoform is coded by distinct genes (Stapleton et al., 1997, Thornton et al., 1998, Cheung et al., 2000) and differences in regulation by AMP between the numerous heterotrimeric combinations have also been observed (Salt et al., 1998, Cheung et al., 2000). A representation
5′ Adenosine monophosphate activated protein kinase kinases
In addition to allosteric activation by increases in the cellular AMP:ATP ratio, AMPK activation is dependent on phosphorylation of Thr172 on the catalytic α subunit by upstream AMPK kinases (AMPKK). AMPKK's identified to date are LKB-1 (Woods et al., 2003), the Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) (Hawley et al., 2005) and the transforming growth factor — β-activated kinase (TAK1) (Momcilovic et al., 2006).
LKB-1, the most investigated AMPKK to date, was originally identified
5′ Adenosine monophosphate activated protein kinase function
AMPK activity is increased in response to environmental stresses including exercise, starvation, inflammation and hypoxia. Key metabolic actions of AMPK, through the phosphorylation of myriad downstream substrates include: stimulating fatty acid oxidation and glucose uptake in skeletal muscle and heart, reducing fatty acid synthesis, cholesterol production and gluconeogenesis in liver, reducing fatty acid synthesis and lipolysis in adipocytes, inhibiting insulin secretion from pancreatic β
5′ Adenosine monophosphate activated protein kinase in the vascular endothelium
In the vascular endothelium, both α subunits of AMPK are expressed (Zou et al., 2004, Xie, Dong, et al., 2006, Fisslthaler and Fleming, 2009) although AMPKα1 is expressed to a much greater extent than AMPKα2. The α2 subunit however, has important physiological effects such as pro-angiogenic effects and endothelial cell differentiation under conditions of hypoxia (Nagata et al., 2003). In human cultured endothelial cells AMPK isoform expression can vary markedly from donor to donor and this can
5′ Adenosine monophosphate activated protein kinase in vascular smooth muscle
In vascular smooth muscle cells (VSMC), both catalytic α isoforms are found although the proportions of α subunits differ between different arteries (Rubin et al., 2005). In mouse aorta, an artery which has been used in many studies, it is the α1 subunit that is predominantly expressed (Goirand et al., 2007).
The role of AMPK in VSMC remains poorly characterized. However AMPK activation in these cells has recently been implicated in vasorelaxation. AICAR-mediated AMPK activation induced
Endothelial dysfunction
Recent research has identified activation of AMPK as a potential target in atherosclerosis due to its reported vascular protective (Zou & Wu, 2008) and anti-atherosclerotic properties (Motoshima et al., 2006). Much of this evidence has come from studies which have examined the consequences of AMPK dysregulation and the strong link between diabetes, metabolic dysfunction and macrovascular disease. Endothelial dysfunction and inflammatory cell adhesion are one of the earliest events in
Therapeutic agents and 5′ adenosine monophosphate activated protein kinase activation
As alluded to earlier in this review, a number of commonly and widely prescribed drugs owe at least some of their therapeutic activity to activation of AMPK (overviewed in Fig. 2). Good experimental evidence exists for metformin (Zhou et al., 2001), the thiazolidinediones (Boyle et al., 2008) and the statins (Sun et al., 2006). In addition, there is some evidence that angiotensin II may inactivate AMPK and that this may underlie the deleterious effects of AT II on vascular remodelling (Stuck et
5′ Adenosine monophosphate activated protein kinase activating agents
In addition to the drugs discussed previously which owe some of their therapeutic action to activating AMPK, there may be potential for a drug which specifically activates AMPK. Indeed, AICAR has been trialed for intravenous use to reduce ischaemia–reperfusion injury (Drew & Kingwell, 2008) where it has been shown to reduce infarct size but not to improve overall outcome (Ross et al., 2005). The mechanism appears to be via activation of AMPK in the vasculature and myocardium which switches on
Conclusions
In conclusion, there is a wide body of evidence suggesting that a selective and potent agent which activates AMPK would be vasculoprotective. The fact that other agents with vasculoprotective effects such as statins and thiazolidinediones can activate AMPK lends weight to AMPK as a therapeutic target in cardiometabolic disease. An overview of the vascular effects of AMPK activation, sites of action of some AMPK activating agents and potential therapeutic targets is shown in Fig. 2. As a dual
References (167)
- et al.
Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel
Eur J Pharmacol
(2010) The structure of a domain common to archaebacteria and the homocystinuria disease protein
TIBS
(1997)- et al.
Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase
J Biol Chem
(2008) - et al.
Modulation of PPAR activity via phosphorylation
Biochim Biophys Acta
(2007) - et al.
AICAR induces cyclooxygenase-2 expression through AMP-activated protein kinase-transforming growth factor-beta-activated kinase 1-p38 mitogen-activated protein kinase signaling pathway
Biochem Pharmacol
(2010) - et al.
AMP-activated protein kinase phosphorylation of endothelial NO synthase
FEBS Lett
(1999) - et al.
Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo
J Biol Chem
(2008) - et al.
Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome
Cell Metab
(2006) - et al.
Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase
J Biol Chem
(1998) - et al.
Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes
J Biol Chem
(2005)
5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC
FEBS Lett
Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents
J Diab Complications
Inducible nitric oxide synthase mediates prostaglandin h2 synthase nitration and suppresses eicosanoid production
Am J Pathol
Activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by adenosine 5′-monophosphate
Biochem Biophys Res Comm
C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest
J Biol Chem
The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct pathways
J Biol Chem
Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase
J Biol Chem
High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells
FEBS Lett
Characterization of the AMP-activated protein kinase kinase from rat liver, and identification of threonine-172 as the major site at which it phosphorylates and activates AMP-activated protein kinase
J Biol Chem
Calmodulin-dependent protein kinase kinase-[beta] is an alternative upstream kinase for AMP-activated protein kinase
Cell Metab
Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation
Cell Metab
5′-AMP activates the AMP-activated protein kinase cascade, and Ca/calmodulin activates the calmodulin-dependent protein kinase I cascade, via three independent mechanisms
J Biol Chem
AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase
J Biol Chem
Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491
J Biol Chem
A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias
Curr Biol
Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP
J Biol Chem
AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism
Cell Metab
Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells
J Biol Chem
Peroxynitrite increases protein phosphatase activity and promotes the interaction of phospholamban with protein phosphatase 2a in the myocardium
Nitric Oxide
High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′AMP-activated protein kinase inhibition of acetyl-CoA carboxylase
J Biol Chem
Purification and properties of a kinase which phosphorylates and inactivates acetyl-CoA carboxylase
J Biol Chem
Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice
J Biol Chem
AICAR stimulates adiponectin and inhibits cytokines in adipose tissue
Biochem Biophys Res Commun
Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin
J Biol Chem
Metformin reduces blood pressure and restores endothelial function in aorta of streptozotocin-induced diabetic rats
Life Sci
Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli
Biochem Biophys Res Commun
AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues
Med Hypotheses
Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro
J Biol Chem
Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site
Protein Sci
AMP-activated protein kinase in the heart: role during health and disease
Circ Res
Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD
EMBO J
Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide
Proc Natl Acad Sci USA
Diabetes and atherosclerosis: epidemiology, pathophysiology, and management
JAMA
Characterization and regulation of reductase kinase, a protein kinase that modulates the enzymic activity of 3-hydroxy-3 methylglutaryl-coenzyme A reductase
Proc Natl Acad Sci USA
AMP-activated protein kinase activator A-769662 is an inhibitor of the Na+–K+-ATPase
Am J Physiol Cell Physiol
MO25 isoforms interact with the STE20-related pseudokinase STRADalpha/beta and enhance their ability to bind, activate and localise the LKB1 tumour suppressor in the cytoplasm
EMBO J
Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion
Arterioscler Thromb Vasc Biol
A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis
FEBS Lett
Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5
J Endocrinol
Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism
Arterioscler Thromb Vasc Biol
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