Associate Editor: R.M. Wadsworth
AMPK and vasculoprotection

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Abstract

AMP-activated protein kinase (AMPK) is proposed to be a key regulator of cellular and organismal metabolism and has reported vasculoprotective effects. In addition, many therapeutic agents used in the treatment of diabetes and atherosclerosis such as metformin, thiazolidinediones and statins may exert their vasculoprotective effects through activation of AMPK. Activation of AMPK has a number of potentially beneficial anti-atherosclerotic effects including reducing adhesion of inflammatory cells to the blood vessel endothelium, reducing lipid accumulation and the proliferation of inflammatory cells caused by oxidised lipids, stimulation of gene expression responsible for cellular antioxidant defenses and stimulation of enzymes responsible for nitric oxide formation. In humans and animals the AMPK cascade triggers vascular protective mechanisms that have been shown to reduce myocardial ischaemic injury and mutations in AMPK can cause familial hypertrophic cardiomyopathy. Taken together, these data suggest that activation and function of AMPK contributes to cardiovascular health. In this review we propose to focus on the vasculoprotective effects of AMPK, the evidence for AMPK activation with currently used therapeutic agents and the potential for agents which specifically activate AMPK as a treatment for vascular disease.

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

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