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      AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

      , , ,
      Clinical Science (London, England : 1979)
      Portland Press Ltd.
      5-amino-4-imidazolecarboxamide riboside-1-β-D-ribofuranoside (AICAR), AMP-activated protein kinase (AMPK), cardiovascular disease, insulin resistance, metformin, obesity, ACC, acetyl-CoA carboxylase, AICAR, 5-amino-4-imidazolecarboxamide riboside-1-β-D-ribofuranoside, AMPK, AMP-activated protein kinase, CaMK, Ca2+/calmodulin-dependent protein kinase, CPT-1, carnitine palmitoyltransferase-1, CVD, cardiovascular disease, eEF2, eukaryotic elongation factor 2, eNOS, endothelial NO synthase, GLUT-4, glucose transporter-4, HF, heart failure, CHF, chronic HF, HMG-CoA, 3-hydroxy-3-methyl-CoA, IL-6, interleukin-6, LV, left ventricular, MF, metformin, MI, myocardial infarction, MO25, mouse protein 25, mTOR, mammalian target of rapamycin, NEFA, non-esterified fatty acid (‘free fatty acid’), p70RSK, p70 ribosomal protein S6 kinase, PDH, pyruvate dehydrogenase, PFK-2, phosphofructokinase-2, PPAR-γ, peroxisome-proliferator-activated receptor-γ, PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events, STRAD, Ste20-related adaptor, TNF-α, tumour necrosis factor-α, TZD, thiazolinedione

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          AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca 2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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          Most cited references104

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          Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence.

          E. Ford (2005)
          In recent years, several major organizations have endorsed the concept of the metabolic syndrome and developed working definitions for it. How well these definitions predict the risk for adverse events in people with the metabolic syndrome is only now being learned. The purpose of this study was to summarize the estimates of relative risk for all-cause mortality, cardiovascular disease, and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). The author reviewed prospective studies from July 1998 through August 2004. For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90-1.78) for all-cause mortality, 1.65 (1.38-1.99) for cardiovascular disease, and 2.99 (1.96-4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09-1.74) for all-cause mortality and 1.93 (1.39-2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55-4.38) for coronary heart disease. These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is approximately 6-7% for all-cause mortality, 12-17% for cardiovascular disease, and 30-52% for diabetes. Further research is needed to establish the use of the metabolic syndrome in predicting risk for death, cardiovascular disease, and diabetes in various population subgroups.
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            An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).

            Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.
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              Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.

              We report here a new mitochondrial regulation occurring only in intact cells. We have investigated the effects of dimethylbiguanide on isolated rat hepatocytes, permeabilized hepatocytes, and isolated liver mitochondria. Addition of dimethylbiguanide decreased oxygen consumption and mitochondrial membrane potential only in intact cells but not in permeabilized hepatocytes or isolated mitochondria. Permeabilized hepatocytes after dimethylbiguanide exposure and mitochondria isolated from dimethylbiguanide pretreated livers or animals were characterized by a significant inhibition of oxygen consumption with complex I substrates (glutamate and malate) but not with complex II (succinate) or complex IV (N,N,N',N'-tetramethyl-1, 4-phenylenediamine dihydrochloride (TMPD)/ascorbate) substrates. Studies using functionally isolated complex I obtained from mitochondria isolated from dimethylbiguanide-pretreated livers or rats further confirmed that dimethylbiguanide action was located on the respiratory chain complex I. The dimethylbiguanide effect was temperature-dependent, oxygen consumption decreasing by 50, 20, and 0% at 37, 25, and 15 degrees C, respectively. This effect was not affected by insulin-signaling pathway inhibitors, nitric oxide precursor or inhibitors, oxygen radical scavengers, ceramide synthesis inhibitors, or chelation of intra- or extracellular Ca(2+). Because it is established that dimethylbiguanide is not metabolized, these results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.

                Author and article information

                Clin Sci (Lond)
                Clinical Science (London, England : 1979)
                Portland Press Ltd.
                16 March 2009
                1 April 2009
                : 116
                : Pt 8
                : 607-620
                Division of Medicine and Therapeutics, University of Dundee and Medical School, Ninewells Hospital, Dundee DD1 9SY, Scotland, U.K.
                Author notes
                Correspondence: Professor Chim C. Lang (email c.c.lang@ 123456dundee.ac.uk ).
                © 2009 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 3, References: 135, Pages: 14
                Review Article

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