AMP-activated protein kinase, stress responses and cardiovascular diseases

Clinical Science

Volumn 122, Issue 12, 2012, Pages 555-573

  Wang, Shaobin ^a   Song, Ping ^a   Zou, Ming Hui ^a  

^a UNIVERSITY OF OKLAHOMA COLLEGE OF MEDICINE   (United States)

Author keywords

AMP activated protein kinase (AMPK); Autophagy; Cardiovascular disease; Energy sensor; Metformin; Stress

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; ADENOSINE PHOSPHATE; ADENOSINE TRIPHOSPHATE; AMINO ACID; BERBERINE; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE KINASE; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE KINASE BETA; CATALASE; GAMMA GLUTAMYLTRANSFERASE; GLITAZONE DERIVATIVE; GLUCOSE; GLYCOGEN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ALPHA; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE BETA; MAMMALIAN TARGET OF RAPAMYCIN; MANGANESE SUPEROXIDE DISMUTASE; METFORMIN; NITRIC OXIDE; PEROXYNITRITE; PYRIMIDINE DERIVATIVE; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; RESVERATROL; ROSIGLITAZONE; SUPEROXIDE; THIOREDOXIN; UNCLASSIFIED DRUG; ANTIOXIDANT;

AMINO ACID METABOLISM; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; AUTOPHAGY; CARDIOMYOPATHY; CARDIOVASCULAR DISEASE; CELL ENERGY; CELL POLARITY; CELL PROLIFERATION; CELL SURVIVAL; CELLULAR STRESS RESPONSE; CONGESTIVE HEART FAILURE; DRUG MECHANISM; ENERGY BALANCE; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME STRUCTURE; ENZYME SUBUNIT; EXERCISE; GENOTOXICITY; GLUCOGENESIS; HEART LEFT VENTRICLE HYPERTROPHY; HEART MUSCLE CELL; HEART PROTECTION; HOMEOSTASIS; HUMAN; LIPID DIET; METABOLIC REGULATION; MITOCHONDRIAL RESPIRATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUTRIENT LIMITATION; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY MECHANISM; REVIEW; STRESS; WOLFF PARKINSON WHITE SYNDROME; ANIMAL; ANOXIA; BIOLOGICAL MODEL; GENE EXPRESSION REGULATION; METABOLISM; MITOCHONDRION; MOUSE; OXIDATION REDUCTION REACTION; PHYSIOLOGY;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; ANOXIA; ANTIOXIDANTS; AUTOPHAGY; CARDIOVASCULAR DISEASES; CELL PROLIFERATION; GENE EXPRESSION REGULATION; HUMANS; METFORMIN; MICE; MITOCHONDRIA; MODELS, BIOLOGICAL; NADPH OXIDASE; OXIDATION-REDUCTION; REACTIVE OXYGEN SPECIES;

EID: 84860296724     PISSN: 01435221     EISSN: None     Source Type: Journal    
DOI: 10.1042/CS20110625     Document Type: Review

References (233)

1. Sengupta, S., Peterson, T. R. and Sabatini, D. M. (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors and stress. Mol. Cell 40, 310-322
2. Calabrese, V., Cornelius, C., Mancuso, C., Lentile, R., Stella, A. M. and Butterfield, D. A. (2010) Redox homeostasis and cellular stress response in aging and neurodegeneration. Methods Mol. Biol. 610, 285-308
3. Ciccia, A. and Elledge, S. J. (2010) The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179-204
4. Majmundar, A. J., Wong, W. J. and Simon, M. C. (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294-309
5. Kenyon, C. J. (2010) The genetics of ageing. Nature 464, 504-5126 Hardie, D. G., Hawley, S. A. and Scott, J. W. (2006) AMP-activated protein kinase-development of the energy sensor concept. J. Physiol. 574, 7-15
6. Hardie, D. G. (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol. 8, 774-785
7. Hardie, D. G. and Carling, D. (1997) The AMP-activated protein kinase - fuel gauge of the mammalian cell? Eur. J. Biochem. 246, 259-273
8. Steinberg, G. R. and Kemp, B. E. (2009) AMPK in health and disease. Physiol. Rev. 89, 1025-1078
9. Suter, M., Riek, U., Tuerk, R., Schlattner, U., Wallimann, T. and Neumann, D. (2006) Dissecting the role of 5'-AMP for allosteric stimulation, activation and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281, 32207-32216
10. Pang, T., Xiong, B., Li, J. Y., Qiu, B. Y., Jin, G. Z., Shen, J. K. and Li, J. (2007) Conserved α-helix acts as autoinhibitory sequence in AMP-activated protein kinase α subunits. J. Biol. Chem. 282, 495-506
11. Crute, B. E., Seefeld, K., Gamble, J., Kemp, B. E. and Witters, L. A. (1998) Functional domains of the α1 catalytic subunit of the AMP-activated protein kinase. J. Biol. Chem. 273, 35347-35354
12. Sanders, M. J., Grondin, P. O., Hegarty, B. D., Snowden, M. A. and Carling, D. (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139-148
13. Hurley, R. L., Barre, L. K., Wood, S. D., Anderson, K. A., Kemp, B. E., Means, A. R. and Witters, L. A. (2006) Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J. Biol. Chem. 281, 36662-36672
14. Stapleton, D., Mitchelhill, K. I., Gao, G., Widmer, J., Michell, B. J., Teh, T., House, C. M., Fernandez, C. S., Cox, T., Witters, L. A. and Kemp, B. E. (1996) Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 271, 611-614
15. Morrow, V. A., Foufelle, F., Connell, J. M., Petrie, J. R., Gould, G. W. and Salt, I. P. (2003) Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J. Biol. Chem. 278, 31629-31639
16. Song, P., Wang, S., He, C., Liang, B., Viollet, B. and Zou, M. H. (2011) AMPKα2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circ. Res. 109, 1230-1239
17. Dong, Y., Zhang, M., Liang, B., Xie, Z., Zhao, Z., Asfa, S., Choi, H. C. and Zou, M. H. (2010) Reduction of AMP-activated protein kinase α2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121, 792-803
18. Wang, S., Dale, G. L., Song, P., Viollet, B. and Zou, M. H. (2010) AMPKα1 deletion shortens erythrocyte life span in mice: role of oxidative stress. J. Biol. Chem. 285, 19976-19985
19. Salt, I., Celler, J. W., Hawley, S. A., Prescott, A., Woods, A., Carling, D. and Hardie, D. G. (1998) AMP-activated protein kinase: greater AMP dependence and preferential nuclear localization, of complexes containing the α2 isoform. Biochem. J. 334, 177-187
20. Polekhina, G., Gupta, A., Michell, B. J., van Denderen, B., Murthy, S., Feil, S. C., Jennings, I. G., Campbell, D. J., Witters, L. A., Parker, M.W. et al. (2003) AMPK β subunit targets metabolic stress sensing to glycogen. Curr. Biol. 13, 867-871
21. Woods, A., Cheung, P. C., Smith, F. C., Davison, M. D., Scott, J., Beri, R. K. and Carling, D. (1996) Characterization of AMP-activated protein kinase β and γ subunits. Assembly of the heterotrimeric complex in vitro. J. Biol. Chem. 271, 10282-10290
22. Iseli, T. J., Walter, M., van Denderen, B. J., Katsis, F., Witters, L. A., Kemp, B. E., Michell, B. J. and Stapleton, D. (2005) AMP-activated protein kinase β subunit tethers α and γ subunits via its C-terminal sequence (186-270). J. Biol. Chem. 280, 13395-13400
23. Oakhill, J. S., Chen, Z. P., Scott, J.W., Steel, R., Castelli, L. A., Ling, N., Macaulay, S. L. and Kemp, B. E. (2010) β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc. Natl. Acad. Sci. U.S.A. 107, 19237-19241
24. Xiao, B., Heath, R., Saiu, P., Leiper, F. C., Leone, P., Jing, C., Walker, P. A., Haire, L., Eccleston, J. F., Davis, C. T. et al. (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496-500
25. Cheung, P. C., Salt, I. P., Davies, S. P., Hardie, D. G. and Carling, D. (2000) Characterization of AMP-activated protein kinase γ -subunit isoforms and their role in AMP binding. Biochem. J. 346, 659-669
26. Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F. et al. (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230-233
27. Wu, Y., Song, P., Xu, J., Zhang, M. and Zou, M. H. (2007) Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J. Biol. Chem. 282, 9777-9788
28. Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., Bignell, G., Warren, W., Aminoff, M., Hoglund, P. et al. (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184-187
29. Hawley, S. A., Boudeau, J., Reid, J. L., Mustard, K. J., Udd, L., Makela, T. P., Alessi, D. R. and Hardie, D. G. (2003) Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28
30. Woods, A., Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M. and Carling, D. (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008
31. Xie, Z., Dong, Y., Zhang, J., Scholz, R., Neumann, D. and Zou, M. H. (2009) Identification of the serine 307 of LKB1 as a novel phosphorylation site essential for its nucleocytoplasmic transport and endothelial cell angiogenesis. Mol. Cell. Biol. 29, 3582-3596
32. Baas, A. F., Boudeau, J., Sapkota, G. P., Smit, L., Medema, R., Morrice, N. A., Alessi, D. R. and Clevers, H. C. (2003) Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 22, 3062-3072
33. Boudeau, J., Baas, A. F., Deak, M., Morrice, N. A., Kieloch, A., Schutkowski, M., Prescott, A. R., Clevers, H. C. and Alessi, D. R. (2003) MO25α/β interact with STRADα/β enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 22, 5102-5114
34. Hurley, R. L., Anderson, K. A., Franzone, J. M., Kemp, B. E., Means, A. R. and Witters, L. A. (2005) The Ca2+ /calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060-29066
35. Hawley, S. A., Pan, D. A., Mustard, K. J., Ross, L., Bain, J., Edelman, A. M., Frenguelli, B. G. and Hardie, D. G. (2005) Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9-19
36. Woods, A., Dickerson, K., Heath, R., Hong, S. P., Momcilovic, M., Johnstone, S. R., Carlson, M. and Carling, D. (2005) Ca2+ /calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21-33
37. Momcilovic, M., Hong, S. P. and Carlson, M. (2006) Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J. Biol. Chem. 281, 25336-25343
38. Davies, S. P., Helps, N. R., Cohen, P. T. and Hardie, D. G. (1995) 5'-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C α and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421-42540
39. Ravnskjaer, K., Boergesen, M., Dalgaard, L. T. and Mandrup, S. (2006) Glucose-induced repression of PPARα gene expression in pancreatic β-cells involves PP2A activation and AMPK inactivation. J. Mol. Endocrinol. 36, 289-299
40. Qi, J., Gong, J., Zhao, T., Zhao, J., Lam, P., Ye, J., Li, J. Z., Wu, J., Zhou, H. M. and Li, P. (2008) Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J. 27, 1537-1548
41. Hawley, S. A., Ross, F. A., Chevtzoff, C., Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M. and Hardie, D. G. (2010) Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554-565
42. Klimova, T. and Chandel, N. S. (2008) Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ. 15, 660-666
43. Jibb, L. A. and Richards, J. G. (2008) AMP-activated protein kinase activity during metabolic rate depression in the hypoxic goldfish, Carassius auratus. J. Exp. Biol. 211, 3111-3122
44. Marsin, A. S., Bertrand, L., Rider, M. H., Deprez, J., Beauloye, C., Vincent, M. F., Van den Berghe, G., Carling, D. and Hue, L. (2000) Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10, 1247-1255
45. Liu, C., Liang, B., Wang, Q., Wu, J. and Zou, M.H. (2010) Activation of AMP-activated protein kinase α1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J. Biol. Chem. 285, 15346-15355
46. Hardie, D. G. and Hawley, S. A. (2001) AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays 23, 1112-1119
47. Zou, M. H., Shi, C. and Cohen, R. A. (2002) High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H2 receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 51, 198-203
48. Zou, M. H., Shi, C. and Cohen, R. A. (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Invest. 109, 817-826
49. Zou, M. H., Kirkpatrick, S. S., Davis, B. J., Nelson, J. S., Wiles, W. G. t., Schlattner, U., Neumann, D., Brownlee, M., Freeman, M. B. and Goldman, M. H. (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J. Biol. Chem. 279, 43940-43951
50. Hamanaka, R. B. and Chandel, N. S. (2009) Mitochondrial reactive oxygen species regulate hypoxic signaling. Curr. Opin. Cell Biol. 21, 894-899
51. Laderoute, K. R., Amin, K., Calaoagan, J. M., Knapp, M., Le, T., Orduna, J., Foretz, M. and Viollet, B. (2006) 5'-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol. Cell. Biol. 26, 5336-5347
52. Zou, M. H., Hou, X. Y., Shi, C. M., Kirkpatick, S., Liu, F., Goldman, M. H. and Cohen, R. A. (2003) Activation of 5'-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxiareoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J. Biol. Chem. 278, 34003-34010
53. Xie, Z., Dong, Y., Scholz, R., Neumann, D. and Zou, M. H. (2008) Phosphorylation of LKB1 at serine 428 by protein kinase C-ζ is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation 117, 952-962
54. Mungai, P. T., Waypa, G. B., Jairaman, A., Prakriya, M., Dokic, D., Ball, M. K. and Schumacker, P. T. (2011) Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol. Cell. Biol. 31, 3531-3545
55. Lee, M., Hwang, J. T., Lee, H. J., Jung, S. N., Kang, I., Chi, S. G., Kim, S. S. and Ha, J. (2003) AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J. Biol. Chem. 278, 39653-39661
56. Papandreou, I., Lim, A. L., Laderoute, K. and Denko, N. C. (2008) Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3 and BNIP3L. Cell Death Differ. 15, 1572-1581
57. Goodyear, L. J. (2008) The exercise pill - too good to be true? N. Engl. J. Med. 359, 1842-1844
58. Richter, E. A. and Ruderman, N. B. (2009) AMPK and the biochemistry of exercise: implications for human health and disease. Biochem. J. 418, 261-275
59. Winder, W.W. and Hardie, D. G. (1996) Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am. J. Physiol. 270, E299-E304
60. Mu, J., Barton, E. R. and Birnbaum, M. J. (2003) Selective suppression of AMP-activated protein kinase in skeletal muscle: update on 'lazy mice'. Biochem. Soc. Trans. 31, 236-241
61. Merrill, G. F., Kurth, E. J., Hardie, D. G. and Winder, W. W. (1997) AICA riboside increases AMP-activated protein kinase, fatty acid oxidation and glucose uptake in rat muscle. Am. J. Physiol. 273, E1107-E1112
62. Iglesias, M. A., Ye, J. M., Frangioudakis, G., Saha, A. K., Tomas, E., Ruderman, N. B., Cooney, G. J. and Kraegen, E. W. (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51, 2886-2894
63. Narkar, V. A., Downes, M., Yu, R. T., Embler, E., Wang, Y. X., Banayo, E., Mihaylova, M. M., Nelson, M. C., Zou, Y., Juguilon, H. et al. (2008) AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405-415
64. Suwa, M., Nakano, H. and Kumagai, S. (2003) Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3 and PGC-1 in rat muscles. J. Appl. Physiol. 95, 960-968
65. Rockl, K. S., Hirshman, M. F., Brandauer, J., Fujii, N., Witters, L. A. and Goodyear, L. J. (2007) Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 56, 2062-2069
66. Reference deleted
67. O'Neill, H. M., Maarbjerg, S. J., Crane, J. D., Jeppesen, J., Jorgensen, S. B., Schertzer, J. D., Shyroka, O., Kiens, B., van Denderen, B. J., Tarnopolsky, M. A. et al. (2011) AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl. Acad. Sci. U.S.A. 108, 16092-16097
68. Smerdu, V., Karsch-Mizrachi, I., Campione, M., Leinwand, L. and Schiaffino, S. (1994) Type IIx myosin heavy chain transcripts are expressed in type IIb fibers of human skeletal muscle. Am. J. Physiol. 267, C1723-C1728
69. Holmes, B. F., Kurth-Kraczek, E. J. and Winder, W.W. (1999) Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase and glycogen in muscle. J. Appl. Physiol. 87, 1990-1995
70. Minokoshi, Y., Kim, Y. B., Peroni, O. D., Fryer, L. G., Muller, C., Carling, D. and Kahn, B. B. (2002) Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339-343
71. Steinberg, G. R., Rush, J.W. and Dyck, D. J. (2003) AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am. J. Physiol. Endocrinol. Metab. 284, E648-E654
72. Liao, Y., Takashima, S., Maeda, N., Ouchi, N., Komamura, K., Shimomura, I., Hori, M., Matsuzawa, Y., Funahashi, T. and Kitakaze, M. (2005) Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc. Res. 67, 705-71374
73. Shibata, R., Sato, K., Pimentel, D. R., Takemura, Y., Kihara, S., Ohashi, K., Funahashi, T., Ouchi, N. and Walsh, K. (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat. Med. 11, 1096-1103
74. Dasgupta, B. and Milbrandt, J. (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl. Acad. Sci. U.S.A. 104, 7217-7222
75. Han, Y., Wang, Q., Song, P., Zhu, Y. and Zou, M. H. (2010) Redox regulation of the AMP-activated protein kinase. PLoS ONE 5, e15420
76. Lee, Y. S., Kim, W. S., Kim, K. H., Yoon, M. J., Cho, H. J., Shen, Y., Ye, J. M., Lee, C. H., Oh, W. K., Kim, C. T. et al. (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55, 2256-2264
77. Corton, J. M., Gillespie, J. G., Hawley, S. A. and Hardie, D. G. (1995) 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. 229, 558-565
78. Chen, K., Xu, X., Kobayashi, S., Timm, D., Jepperson, T. and Liang, Q. (2011) Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms. J. Biol. Chem. 286, 21993-22006
79. Wang, Q., Liang, B., Shirwany, N. A. and Zou, M. H. (2011) 2-Deoxy-d-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase. PLoS ONE 6, e17234
80. Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N. et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167-1174
81. LeBrasseur, N. K., Kelly, M., Tsao, T. S., Farmer, S. R., Saha, A. K., Ruderman, N. B. and Tomas, E. (2006) Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am. J. Physiol. Endocrinol. Metab. 291, E175-E181
82. Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R. et al. (2006) Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403-416
83. Anderson, S. N., Cool, B. L., Kifle, L., Chiou, W., Egan, D. A., Barrett, L.W., Richardson, P. L., Frevert, E. U., Warrior, U., Kofron, J. L. and Burns, D. J. (2004) Microarrayed compound screening (microARCS) to identify activators and inhibitors of AMP-activated protein kinase. J. Biomol. Screen. 9, 112-121
84. Pang, T., Zhang, Z. S., Gu, M., Qiu, B. Y., Yu, L. F., Cao, P. R., Shao, W., Su, M. B., Li, J. Y., Nan, F. J. and Li, J. (2008) Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J. Biol. Chem. 283, 16051-16060
85. Guigas, B., Bertrand, L., Taleux, N., Foretz, M., Wiernsperger, N., Vertommen, D., Andreelli, F., Viollet, B. and Hue, L. (2006) 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes 55, 865-874
86. Foretz, M., Hebrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F. and Viollet, B. (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355-2369
87. Long, Y. C. and Zierath, J. R. (2006) AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116, 1776-1783
88. Kraegen, E.W., Saha, A. K., Preston, E., Wilks, D., Hoy, A. J., Cooney, G. J. and Ruderman, N. B. (2006) Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. Am. J. Physiol. Endocrinol. Metab. 290, E471-E479
89. Zang, M., Zuccollo, A., Hou, X., Nagata, D., Walsh, K., Herscovitz, H., Brecher, P., Ruderman, N. B. and Cohen, R. A. (2004) AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J. Biol. Chem. 279, 47898-47905
90. Wojtaszewski, J. F., Jorgensen, S. B., Hellsten, Y., Hardie, D. G. and Richter, E. A. (2002) Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes 51, 284-292
91. McBride, A., Ghilagaber, S., Nikolaev, A. and Hardie, D. G. (2009) The glycogen-binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9, 23-34
92. Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S. and Andreelli, F. (2010) AMPK inhibition in health and disease. Crit. Rev. Biochem. Mol. Biol. 45, 276-295
93. Ropelle, E. R., Pauli, J. R., Fernandes, M. F., Rocco, S. A., Marin, R. M., Morari, J., Souza, K. K., Dias, M. M., Gomes-Marcondes, M. C., Gontijo, J. A. et al. (2008) A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes 57, 594-605
94. Wullschleger, S., Loewith, R. and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484
95. Bain, J., Plater, L., Elliott, M., Shpiro, N., Hastie, C. J., McLauchlan, H., Klevernic, I., Arthur, J. S., Alessi, D. R. and Cohen, P. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408, 297-315
96. Vogt, J., Traynor, R. and Sapkota, G. P. (2011) The specificities of small molecule inhibitors of the TGFss and BMP pathways. Cell. Signalling 23, 1831-1842
97. Fontana, L., Partridge, L. and Longo, V. D. (2010) Extending healthy life span - from yeast to humans. Science 328, 321-326
98. Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., Allison, D. B., Cruzen, C., Simmons, H. A., Kemnitz, J.W. and Weindruch, R. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201-204
99. Ashrafi, K., Lin, S. S., Manchester, J. K. and Gordon, J. I. (2000) Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes Dev. 14, 1872-1885
100. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. and Curtis, R. (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18, 3004-3009
101. Reznick, R. M., Zong, H., Li, J., Morino, K., Moore, I. K., Yu, H. J., Liu, Z. X., Dong, J., Mustard, K. J., Hawley, S. A. et al. (2007) Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 5, 151-156
102. Sakamoto, K., McCarthy, A., Smith, D., Green, K. A., Grahame Hardie, D., Ashworth, A. and Alessi, D. R. (2005) Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24, 1810-1820
103. Canto, C. and Auwerx, J. (2011) Calorie restriction: is AMPK a key sensor and effector? Physiology 26, 214-224
104. Lin, S. J., Defossez, P. A. and Guarente, L. (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126-2128
105. Houtkooper, R. H., Williams, R. W. and Auwerx, J. (2010) Metabolic networks of longevity. Cell 142, 9-14107
106. Um, J. H., Park, S. J., Kang, H., Yang, S., Foretz, M., McBurney, M.W., Kim, M. K., Viollet, B. and Chung, J. H. (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59, 554-563
107. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D.W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L. L. et al. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196
108. Canto, C., Gerhart-Hines, Z., Feige, J. N., Lagouge, M., Noriega, L., Milne, J. C., Elliott, P. J., Puigserver, P. and Auwerx, J. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056-1060
109. Lage, R., Dieguez, C., Vidal-Puig, A. and Lopez, M. (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol. Med. 14, 539-549
110. McGee, S. L., van Denderen, B. J., Howlett, K. F., Mollica, J., Schertzer, J. D., Kemp, B. E. and Hargreaves, M. (2008) AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57, 860-867
111. Chopra, A. R., Kommagani, R., Saha, P., Louet, J. F., Salazar, C., Song, J., Jeong, J., Finegold, M., Viollet, B., Demayo, F. et al. (2011) Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption. Cell Metab. 13, 35-43
112. Inoki, K., Zhu, T. and Guan, K. L. (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590
113. Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E. and Shaw, R. J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226
114. Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S. R., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R. et al. (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461
115. Schulz, T. J., Zarse, K., Voigt, A., Urban, N., Birringer, M. and Ristow, M. (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280-293
116. Mair, W., Morantte, I., Rodrigues, A. P., Manning, G., Montminy, M., Shaw, R. J. and Dillin, A. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404-408
117. Fujii, N., Jessen, N. and Goodyear, L. J. (2006) AMP-activated protein kinase and the regulation of glucose transport. Am. J. Physiol. Endocrinol. Metab. 291, E867-E877
118. Fujii, N., Aschenbach, W. G., Musi, N., Hirshman, M. F. and Goodyear, L. J. (2004) Regulation of glucose transport by the AMP-activated protein kinase. Proc. Nutr. Soc. 63, 205-210
119. Jager, S., Handschin, C., St-Pierre, J. and Spiegelman, B. M. (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. U.S.A. 104, 12017-12022
120. Garcia-Roves, P. M., Osler, M. E., Holmstrom, M. H. and Zierath, J. R. (2008) Gain-of-function R225Q mutation in AMP-activated protein kinase γ 3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724-35734
121. Orci, L., Cook, W. S., Ravazzola, M., Wang, M. Y., Park, B. H., Montesano, R. and Unger, R. H. (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc. Natl. Acad. Sci. U.S.A. 101, 2058-2063
122. Wu, X., Motoshima, H., Mahadev, K., Stalker, T. J., Scalia, R. and Goldstein, B. J. (2003) Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 52, 1355-1363
123. Viollet, B., Guigas, B., Leclerc, J., Hebrard, S., Lantier, L., Mounier, R., Andreelli, F. and Foretz, M. (2009) AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol. 196, 81-98
124. Andreelli, F., Foretz, M., Knauf, C., Cani, P. D., Perrin, C., Iglesias, M. A., Pillot, B., Bado, A., Tronche, F., Mithieux, G. et al. (2006) Liver adenosine monophosphate-activated kinase-α2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 147, 2432-2441
125. Lochhead, P. A., Salt, I. P., Walker, K. S., Hardie, D. G. and Sutherland, C. (2000) 5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49, 896-903
126. Horike, N., Sakoda, H., Kushiyama, A., Ono, H., Fujishiro, M., Kamata, H., Nishiyama, K., Uchijima, Y., Kurihara, Y., Kurihara, H. and Asano, T. (2008) AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3β and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J. Biol. Chem. 283, 33902-33910
127. Viollet, B., Foretz, M., Guigas, B., Horman, S., Dentin, R., Bertrand, L., Hue, L. and Andreelli, F. (2006) Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J. Physiol. 574, 41-53
128. Daval, M., Foufelle, F. and Ferre, P. (2006) Functions of AMP-activated protein kinase in adipose tissue. J. Physiol. 574, 55-62
129. Salt, I. P., Johnson, G., Ashcroft, S. J. and Hardie, D. G. (1998) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic β cells and may regulate insulin release. Biochem. J. 335, 533-539
130. da Silva Xavier, G., Leclerc, I., Salt, I. P., Doiron, B., Hardie, D. G., Kahn, A. and Rutter, G. A. (2000) Role of AMP-activated protein kinase in the regulation by glucose of islet β cell gene expression. Proc. Natl. Acad. Sci. U.S.A. 97, 4023-4028
131. Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y. B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M. J. et al. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569-574
132. Sies, H. (2007) Biological redox systems and oxidative stress. Cell. Mol. Life Sci. 64, 2181-2188
133. Jones, D. P. (2008) Radical-free biology of oxidative stress. Am. J. Physiol. Cell Physiol 295, C849-C868
134. Lamberts, R. R., Onderwater, G., Hamdani, N., Vreden, M. J., Steenhuisen, J., Eringa, E. C., Loer, S. A., Stienen, G. J. and Bouwman, R. A. (2009) Reactive oxygen species-induced stimulation of 5'AMP-activated protein kinase mediates sevoflurane-induced cardioprotection. Circulation 120, S10-S15
135. Toyoda, T., Hayashi, T., Miyamoto, L., Yonemitsu, S., Nakano, M., Tanaka, S., Ebihara, K., Masuzaki, H., Hosoda, K., Inoue, G. et al. (2004) Possible involvement of the α1 isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 287, E166-E173
136. Emerling, B. M., Weinberg, F., Snyder, C., Burgess, Z., Mutlu, G. M., Viollet, B., Budinger, G. R. and Chandel, N. S. (2009) Hypoxic activation of AMPK is dependent on mitochondrial ROS but independent of an increase in AMP/ATP ratio. Free Radical Biol. Med. 46, 1386-1391
137. Choi, S. L., Kim, S. J., Lee, K. T., Kim, J., Mu, J., Birnbaum, M. J., Soo Kim, S. and Ha, J. (2001) The regulation of AMP-activated protein kinase by H2O2. Biochem. Biophys. Res. Commun. 287, 92-97
138. Zmijewski, J. W., Banerjee, S., Bae, H., Friggeri, A., Lazarowski, E. R. and Abraham, E. (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J. Biol. Chem. 285, 33154-33164140
139. Xie, Z., Dong, Y., Zhang, M., Cui, M. Z., Cohen, R. A., Riek, U., Neumann, D., Schlattner, U. and Zou, M. H. (2006) Activation of protein kinase Cζ by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells. J. Biol. Chem. 281, 6366-6375
140. Lassegue, B. and Griendling, K. K. (2010) NADPH oxidases: functions and pathologies in the vasculature. Arterioscler. Thromb. Vasc. Biol. 30, 653-661
141. Guzik, T. J., Mussa, S., Gastaldi, D., Sadowski, J., Ratnatunga, C., Pillai, R. and Channon, K. M. (2002) Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 105, 1656-1662
142. Gao, L. and Mann, G. E. (2009) Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovasc. Res. 82, 9-20
143. Brandes, R. P., Weissmann, N. and Schroder, K. (2010) NADPH oxidases in cardiovascular disease. Free Radical Biol. Med. 49, 687-706
144. Alba, G., El Bekay, R., Alvarez-Maqueda, M., Chacon, P., Vega, A., Monteseirin, J., Santa Maria, C., Pintado, E., Bedoya, F. J., Bartrons, R. and Sobrino, F. (2004) Stimulators of AMP-activated protein kinase inhibit the respiratory burst in human neutrophils. FEBS Lett. 573, 219-225
145. Hwang, J., Kleinhenz, D. J., Rupnow, H. L., Campbell, A. G., Thule, P. M., Sutliff, R. L. and Hart, C. M. (2007) The PPARγ ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice. Vasc. Pharmacol. 46, 456-462
146. Piwkowska, A., Rogacka, D., Jankowski, M., Dominiczak, M. H., Stepinski, J. K. and Angielski, S. (2010) Metformin induces suppression of NAD(P)H oxidase activity in podocytes. Biochem. Biophys. Res. Commun. 393, 268-273
147. Wang, S., Zhang, M., Liang, B., Xu, J., Xie, Z., Liu, C., Viollet, B., Yan, D. and Zou, M. H. (2010) AMPKα2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ. Res. 106, 1117-1128
148. Schuhmacher, S., Foretz, M., Knorr, M., Jansen, T., Hortmann, M., Wenzel, P., Oelze, M., Kleschyov, A. L., Daiber, A., Keaney, Jr, J. F. et al. (2011) α1AMP-activated protein kinase preserves endothelial function during chronic angiotensin II treatment by limiting Nox2 upregulation. Arterioscler. Thromb. Vasc. Biol. 31, 560-566
149. Naik, E. and Dixit, V. M. (2011) Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J. Exp. Med. 208, 417-420
150. Arsenijevic, D., Onuma, H., Pecqueur, C., Raimbault, S., Manning, B. S., Miroux, B., Couplan, E., Alves-Guerra, M. C., Goubern, M., Surwit, R. et al. (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat. Genet. 26, 435-439
151. Leloup, C., Casteilla, L., Carriere, A., Galinier, A., Benani, A., Carneiro, L. and Penicaud, L. (2011) Balancing mitochondrial redox signaling: a key point in metabolic regulation. Antioxid. Redox Signaling 14, 519-530
152. Brand, M. D. and Esteves, T. C. (2005) Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2, 85-93
153. Xie, Z., Zhang, J., Wu, J., Viollet, B. and Zou, M. H. (2008) Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes 57, 3222-3230
154. Andrews, Z. B., Liu, Z. W., Walllingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschop, M. H., Shanabrough, M., Cline, G., Shulman, G. I., Coppola, A., Gao, X. B., Horvath, T. L. and Diano, S. (2008) UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846-851
155. Wang, Y., Nishi, M., Doi, A., Shono, T., Furukawa, Y., Shimada, T., Furuta, H., Sasaki, H. and Nanjo, K. (2010) Ghrelin inhibits insulin secretion through the AMPK-UCP2 pathway in β cells. FEBS Lett 584, 1503-1508
156. Calegari, V. C., Zoppi, C. C., Rezende, L. F., Silveira, L. R., Carneiro, E. M. and Boschero, A. C. (2011) Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets. J. Endocrinol. 208, 257-264
157. Beall, C., Piipari, K., Al-Qassab, H., Smith, M. A., Parker, N., Carling, D., Viollet, B., Withers, D. J. and Ashford, M. L. (2010) Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia. Biochem. J. 429, 323-333
158. Wallace, D. C. (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359-407
159. Kim, I., Rodriguez-Enriquez, S. and Lemasters, J. J. (2007) Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462, 245-253
160. Wu, J. J., Quijano, C., Chen, E., Liu, H., Cao, L., Fergusson, M. M., Rovira, II, Gutkind, S., Daniels, M. P., Komatsu, M. and Finkel, T. (2009) Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging 1, 425-437
161. Mathew, R., Karp, C. M., Beaudoin, B., Vuong, N., Chen, G., Chen, H. Y., Bray, K., Reddy, A., Bhanot, G., Gelinas, C. et al. (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062-1075
162. Sandoval, H., Thiagarajan, P., Dasgupta, S. K., Schumacher, A., Prchal, J. T., Chen, M. and Wang, J. (2008) Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232-235
163. Mortensen, M., Ferguson, D. J. and Simon, A. K. (2010) Mitochondrial clearance by autophagy in developing erythrocytes: clearly important, but just how much so? Cell Cycle 9, 1901-1906
164. Roach, P. J. (2011) AMPK→ULK1→autophagy. Mol. Cell. Biol. 31, 3082-3084
165. Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M. T., Brickey, W. J. and Ting, J. P. (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408-415
166. Li, X. N., Song, J., Zhang, L., LeMaire, S. A., Hou, X., Zhang, C., Coselli, J. S., Chen, L., Wang, X. L., Zhang, Y. and Shen, Y. H. (2009) Activation of the AMPK-FOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin. Diabetes 58, 2246-2257
167. Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T. and Araki, E. (2006) Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes 55, 120-127
168. Colombo, S. L. and Moncada, S. (2009) AMPKα1 regulates the antioxidant status of vascular endothelial cells. Biochem. J. 421, 163-169
169. Grana, X. and Reddy, E. P. (1995) Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclindependent kinase inhibitors (CKIs). Oncogene 11, 211-219
170. Imamura, K., Ogura, T., Kishimoto, A., Kaminishi, M. and Esumi, H. (2001) Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-β-dribofuranoside, in a human hepatocellular carcinoma cell line. Biochem. Biophys. Res. Commun. 287, 562-567172
171. Igata, M., Motoshima, H., Tsuruzoe, K., Kojima, K., Matsumura, T., Kondo, T., Taguchi, T., Nakamaru, K., Yano, M., Kukidome, D. et al. (2005) Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ. Res. 97, 837-844
172. Bolster, D. R., Crozier, S. J., Kimball, S. R. and Jefferson, L. S. (2002) AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 277, 23977-23980
173. Xiang, X., Saha, A. K., Wen, R., Ruderman, N. B. and Luo, Z. (2004) AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. Biochem. Biophys. Res. Commun. 321, 161-167
174. Henin, N., Vincent, M. F., Gruber, H. E. and Van den Berghe, G. (1995) Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. FASEB J. 9, 541-546
175. Jones, R. G., Plas, D. R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M. J. and Thompson, C. B. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283-293
176. Dagon, Y., Avraham, Y. and Berry, E. M. (2006) AMPK activation regulates apoptosis, adipogenesis and lipolysis by eIF2α in adipocytes. Biochem. Biophys. Res. Commun. 340, 43-47
177. Santidrian, A. F., Gonzalez-Girones, D. M., Iglesias-Serret, D., Coll-Mulet, L., Cosialls, A. M., de Frias, M., Campas, C., Gonzalez-Barca, E., Alonso, E., Labi, V. et al. (2010) AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. Blood 116, 3023-3032
178. Hwang, J. T., Kwak, D. W., Lin, S. K., Kim, H. M., Kim, Y. M. and Park, O. J. (2007) Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway. Ann. N.Y. Acad. Sci. 1095, 441-448
179. Hwang, J. T., Kwon, D. Y., Park, O. J. and Kim, M. S. (2008) Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr. 2, 323-326
180. Asai, T., Liu, Y., Bae, N. and Nimer, S. D. (2011) The p53 tumor suppressor protein regulates hematopoietic stem cell fate. J. Cell Physiol. 226, 2215-2221
181. Miyashita, T. and Reed, J. C. (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293-299
182. Moll, U. M. and Zaika, A. (2001) Nuclear and mitochondrial apoptotic pathways of p53. FEBS Lett 493, 65-69
183. Kuma, A. and Mizushima, N. (2010) Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Sem. Cell Dev. Biol. 21, 683-690
184. Crighton, D., Wilkinson, S., O'Prey, J., Syed, N., Smith, P., Harrison, P. R., Gasco, M., Garrone, O., Crook, T. and Ryan, K. M. (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121-134
185. Karantza-Wadsworth, V., Patel, S., Kravchuk, O., Chen, G., Mathew, R., Jin, S. and White, E. (2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21, 1621-1635
186. Mathew, R., Karantza-Wadsworth, V. and White, E. (2007) Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967
187. Shirwany, N. A. and Zou, M. H. (2010) AMPK in cardiovascular health and disease. Acta Pharmacol. Sin. 31, 1075-1084
188. Gollob, M. H., Green, M. S., Tang, A. S. and Roberts, R. (2002) PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease and cardiac hypertrophy. Curr. Opin. Cardiol. 17, 229-234
189. MacRae, C. A., Ghaisas, N., Kass, S., Donnelly, S., Basson, C. T., Watkins, H. C., Anan, R., Thierfelder, L. H., McGarry, K., Rowland, E. et al. (1995) Familial Hypertrophic cardiomyopathy withWolff-Parkinson- White syndrome maps to a locus on chromosome 7q3. J. Clin. Invest. 96, 1216-1220
190. Blair, E., Redwood, C., Ashrafian, H., Oliveira, M., Broxholme, J., Kerr, B., Salmon, A., Ostman-Smith, I. and Watkins, H. (2001) Mutations in the γ 2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215-1220
191. Gollob, M. H., Green, M. S., Tang, A. S., Gollob, T., Karibe, A., Ali Hassan, A. S., Ahmad, F., Lozado, R., Shah, G., Fananapazir, L. et al. (2001) Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N. Engl. J. Med. 344, 1823-1831
192. Arad, M., Seidman, C. E. and Seidman, J. G. (2007) AMP-activated protein kinase in the heart: role during health and disease. Circ. Res. 100, 474-488
193. Arad, M., Benson, D.W., Perez-Atayde, A. R., McKenna, W. J., Sparks, E. A., Kanter, R. J., McGarry, K., Seidman, J. G. and Seidman, C. E. (2002) Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109, 357-362
194. Davies, J. K., Wells, D. J., Liu, K., Whitrow, H. R., Daniel, T. D., Grignani, R., Lygate, C. A., Schneider, J. E., Noel, G., Watkins, H. and Carling, D. (2006) Characterization of the role of γ 2 R531G mutation in AMP-activated protein kinase in cardiac hypertrophy and Wolff-Parkinson-White syndrome. Am. J. Physiol. Heart Circ. Physiol 290, H1942-H1951
195. Arad, M., Moskowitz, I. P., Patel, V. V., Ahmad, F., Perez-Atayde, A. R., Sawyer, D. B., Walter, M., Li, G. H., Burgon, P. G., Maguire, C. T. et al. (2003) Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation 107, 2850-2856
196. Sidhu, J. S., Rajawat, Y. S., Rami, T. G., Gollob, M. H., Wang, Z., Yuan, R., Marian, A. J., DeMayo, F. J., Weilbacher, D., Taffet, G. E. et al. (2005) Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. Circulation 111, 21-29
197. Patel, V. V., Arad, M., Moskowitz, I. P., Maguire, C. T., Branco, D., Seidman, J. G., Seidman, C. E. and Berul, C. I. (2003) Electrophysiologic characterization and postnatal development of ventricular pre-excitation in a mouse model of cardiac hypertrophy and Wolff-Parkinson- White syndrome. J. Am. Coll. Cardiol. 42, 942-951
198. Arad, M., Maron, B. J., Gorham, J. M., Johnson, Jr, W. H., Saul, J. P., Perez-Atayde, A. R., Spirito, P., Wright, G. B., Kanter, R. J., Seidman, C. E. and Seidman, J. G. (2005) Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N. Engl. J. Med. 352, 362-372
199. Carattino, M. D., Edinger, R. S., Grieser, H. J., Wise, R., Neumann, D., Schlattner, U., Johnson, J. P., Kleyman, T. R. and Hallows, K. R. (2005) Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells. J. Biol. Chem. 280, 17608-17616
200. Hallows, K. R., Raghuram, V., Kemp, B. E., Witters, L. A. and Foskett, J. K. (2000) Inhibition of cystic fibrosis transmembrane conductance regulator by novel interaction with the metabolic sensor AMP-activated protein kinase. J. Clin. Invest. 105, 1711-1721
201. Kalyanaraman, B., Joseph, J., Kalivendi, S., Wang, S., Konorev, E. and Kotamraju, S. (2002) Doxorubicin-induced apoptosis: implications in cardiotoxicity. Mol. Cell. Biochem. 234-235, 119-124
202. Tokarska-Schlattner, M., Zaugg, M., da Silva, R., Lucchinetti, E., Schaub, M. C., Wallimann, T. and Schlattner, U. (2005) Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am. J. Physiol. Heart Circ. Physiol. 289, H37-H47
203. Asensio-Lopez, M. C., Lax, A., Pascual-Figal, D. A., Valdes, M. and Sanchez-Mas, J. (2011) Metformin protects against doxorubicin-induced cardiotoxicity: Involvement of the adiponectin cardiac system. Free Radical Biol. Med. 51, 1861-1871205
204. Konishi, M., Haraguchi, G., Ohigashi, H., Ishihara, T., Saito, K., Nakano, Y. and Isobe, M. (2011) Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation. Cardiovasc. Res. 89, 309-319
205. Russell, III, R. R., Li, J., Coven, D. L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F. J., Mu, J., Birnbaum, M. J. and Young, L. H. (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis and injury. J. Clin. Invest. 114, 495-503
206. Xie, Z., Lau, K., Eby, B., Lozano, P., He, C., Pennington, B., Li, H., Rathi, S., Dong, Y., Tian, R. et al. (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60, 1770-1778
207. Xie, Z., He, C. and Zou, M. H. (2011) AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. Autophagy 7, 1254-1255
208. Hansson, G. K. (2005) Inflammation, atherosclerosis and coronary artery disease. N. Engl. J. Med. 352, 1685-1695
209. Hotamisligil, G. S. (2006) Inflammation and metabolic disorders. Nature 444, 860-867
210. Zhao, X., Zmijewski, J.W., Lorne, E., Liu, G., Park, Y. J., Tsuruta, Y. and Abraham, E. (2008) Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L497-L504
211. Akbar, D. H. (2003) Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 20, 215-218
212. Gauthier, M. S., O'Brien, E. L., Bigornia, S., Mott, M., Cacicedo, J. M., Xu, X. J., Gokce, N., Apovian, C. and Ruderman, N. (2011) Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans. Biochem. Biophys. Res. Commun. 404, 382-387
213. Sag, D., Carling, D., Stout, R. D. and Suttles, J. (2008) Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an antiinflammatory functional phenotype. J. Immunol. 181, 8633-8641
214. Katerelos, M., Mudge, S. J., Stapleton, D., Auwardt, R. B., Fraser, S. A., Chen, C. G., Kemp, B. E. and Power, D.A. (2010) 5-Aminoimidazole-4-carboxamide ribonucleoside and AMP-activated protein kinase inhibit signalling through NF-κB. Immunol. Cell Biol. 88, 754-760
215. Reference deleted
216. Wang, C., Li, L., Zhang, Z. G., Fan, D., Zhu, Y. and Wu, L. L. (2010) Globular adiponectin inhibits angiotensin II-induced nuclear factor κB activation through AMP-activated protein kinase in cardiac hypertrophy. J. Cell Physiol. 222, 149-155
217. Bess, E., Fisslthaler, B., Fromel, T. and Fleming, I. (2011) Nitric oxide-induced activation of the AMP-activated protein kinase α2 subunit attenuates IκB kinase activity and inflammatory responses in endothelial cells. PLoS ONE 6, e20848
218. Grundy, S. M., Benjamin, I. J., Burke, G. L., Chait, A., Eckel, R. H., Howard, B. V., Mitch, W., Smith, Jr, S. C. and Sowers, J. R. (1999) Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100, 1134-1146
219. Asghar, O., Al-Sunni, A., Khavandi, K., Khavandi, A., Withers, S., Greenstein, A., Heagerty, A. M. and Malik, R. A. (2009) Diabetic cardiomyopathy. Clin. Sci. 116, 741-760
220. (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854-865
221. Masoudi, F. A., Inzucchi, S. E., Wang, Y., Havranek, E. P., Foody, J. M. and Krumholz, H. M. (2005) Thiazolidinediones, metformin and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111, 583-590
222. Eurich, D. T., McAlister, F. A., Blackburn, D. F., Majumdar, S. R., Tsuyuki, R. T., Varney, J. and Johnson, J. A. (2007) Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 335, 497
223. Davis, B. J., Xie, Z., Viollet, B. and Zou, M. H. (2006) Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55, 496-505
224. Lewington, S., Whitlock, G., Clarke, R., Sherliker, P., Emberson, J., Halsey, J., Qizilbash, N., Peto, R. and Collins, R. (2007) Blood cholesterol and vascular mortality by age, sex and blood pressure: a metaanalysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370, 1829-1839
225. Foody, J. M., Shah, R., Galusha, D., Masoudi, F. A., Havranek, E. P. and Krumholz, H. M. (2006) Statins and mortality among elderly patients hospitalized with heart failure. Circulation 113, 1086-1092
226. Sun, W., Lee, T. S., Zhu, M., Gu, C., Wang, Y., Zhu, Y. and Shyy, J. Y. (2006) Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation 114, 2655-2662
227. Choi, H. C., Song, P., Xie, Z., Wu, Y., Xu, J., Zhang, M., Dong, Y., Wang, S., Lau, K. and Zou, M. H. (2008) Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J. Biol. Chem. 283, 20186-20197
228. Li, X., Han, Y., Pang, W., Li, C., Xie, X., Shyy, J. Y. and Zhu, Y. (2008) AMP-activated protein kinase promotes the differentiation of endothelial progenitor cells. Arterioscler. Thromb. Vasc. Biol. 28, 1789-1795
229. Kennedy, D. O., Wightman, E. L., Reay, J. L., Lietz, G., Okello, E. J., Wilde, A. and Haskell, C. F. (2010) Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am. J. Clin. Nutr. 91, 1590-1597
230. Wong, R. H., Howe, P. R., Buckley, J. D., Coates, A. M., Kunz, I. and Berry, N. M. (2011) Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr. Metab. Cardiovasc. Dis. 21, 851-856
231. Bradamante, S., Barenghi, L. and Villa, A. (2004) Cardiovascular protective effects of resveratrol. Cardiovasc. Drug Rev. 22, 169-188
232. Zeng, X. H., Zeng, X. J. and Li, Y. Y. (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am. J. Cardiol. 92, 173-176
233. Kong, W., Wei, J., Abidi, P., Lin, M., Inaba, S., Li, C., Wang, Y., Wang, Z., Si, S., Pan, H. et al. (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat. Med. 10, 1344-1351