AMP-Activated Protein Kinase: An Ubiquitous Signaling Pathway with Key Roles in the Cardiovascular System

Circulation Research

Volumn 120, Issue 11, 2017, Pages 1825-1841

  Salt, Ian P ^a   Hardie, D Grahame ^b  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

AMP activated protein kinase; heart; heart defects (congenital); metabolism; vasculature

Indexed keywords

ENDOTHELIAL NITRIC OXIDE SYNTHASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; REACTIVE OXYGEN METABOLITE;

ANGIOGENESIS; ATHEROSCLEROSIS; BLOOD VESSEL CALCIFICATION; BLOOD VESSEL TONE; CARDIOVASCULAR SYSTEM; CATABOLISM; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; DOWN REGULATION; DRUG MECHANISM; GENE MUTATION; GLYCOGEN ANALYSIS; HEART DISEASE; HEART MUSCLE ISCHEMIA; HUMAN; IN VIVO STUDY; MUSCLE CONTRACTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN STRUCTURE; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION; VASCULAR REMODELING; VASCULITIS; ANIMAL; CARDIOVASCULAR DISEASE; ENZYMOLOGY; PATHOLOGY; PHYSIOLOGY;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; HUMANS; SIGNAL TRANSDUCTION; VASCULAR REMODELING;

EID: 85019662904     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.117.309633     Document Type: Review

References (198)

1. Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing pathway with multiple inputs and outputs. Trends Cell Biol. 2016;26:190-201. doi: 10.1016/j.tcb.2015.10.013.
2. Hardie DG, Ashford ML. AMPK: regulating energy balance at the cellular and whole body levels. Physiology (Bethesda). 2014;29:99-107. doi: 10.1152/physiol.00050.2013.
3. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251-262. doi: 10.1038/nrm3311.
4. Daskalopoulos EP, Dufeys C, Beauloye C, Bertrand L, Horman S. AMPK in cardiovascular diseases. EXS. 2016;107:179-201. doi: 10.1007/978-3-319-43589-3-8.
5. Daskalopoulos EP, Dufeys C, Bertrand L, Beauloye C, Horman S. AMPK in cardiac fibrosis and repair: actions beyond metabolic regulation. J Mol Cell Cardiol. 2016;91:188-200. doi: 10.1016/j.yjmcc.2016.01.001.
6. Birk JB, Wojtaszewski JF. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle. J Physiol. 2006;577:1021-1032. doi: 10.1113/jphysiol.2006.120972.
7. Pinter K, Grignani RT, Czibik G, Farza H, Watkins H, Redwood C. Embryonic expression of AMPK subunits and the identification of a novel 2 transcript variant in adult heart. J Mol Cell Cardiol. 2012;53:342-349. doi: 10.1016/j.yjmcc.2012.05.017.
8. Li X, Wang L, Zhou XE, Ke J, de Waal PW, Gu X, Tan MH, Wang D, Wu D, Xu HE, Melcher K. Structural basis of AMPK regulation by adenine nucleotides and glycogen. Cell Res. 2015;25:50-66. doi: 10.1038/ cr.2014.150.
9. Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ. Structural basis of AMPK regulation by small molecule activators. Nat Commun. 2013;4:3017. doi: 10.1038/ncomms4017.
10. Calabrese MF, Rajamohan F, Harris MS, et al. Structural basis for AMPK activation: natural and synthetic ligands regulate kinase activity from opposite poles by different molecular mechanisms. Structure. 2014;22:1161-1172. doi: 10.1016/j.str.2014.06.009.
11. Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA, Green KA, Baba O, Terashima T, Hardie DG. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol. 2003;13:861-866.
12. Polekhina G, Gupta A, Michell BJ, van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW, Kemp BE, Stapleton D. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol. 2003;13:867-871.
13. Bendayan M, Londono I, Kemp BE, Hardie GD, Ruderman N, Prentki M. Association of AMP-activated protein kinase subunits with glycogen particles as revealed in situ by immunoelectron microscopy. J Histochem Cytochem. 2009;57:963-971. doi: 10.1369/jhc.2009.954016.
14. Jørgensen SB, Nielsen JN, Birk JB, Olsen GS, Viollet B, Andreelli F, Schjerling P, Vaulont S, Hardie DG, Hansen BF, Richter EA, Wojtaszewski JF. The alpha2-5'AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes. 2004;53:3074-3081.
15. Bultot L, Guigas B, Von Wilamowitz-Moellendorff A, Maisin L, Vertommen D, Hussain N, Beullens M, Guinovart JJ, Foretz M, Viollet B, Sakamoto K, Hue L, Rider MH. AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem J. 2012;443:193-203. doi: 10.1042/BJ20112026.
16. Langendorf CG, Kemp BE. Choreography of AMPK activation. Cell Res. 2015;25:5-6. doi: 10.1038/cr.2014.163.
17. Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest. 2004;113:274-284. doi: 10.1172/JCI19874.
18. Townley R, Shapiro L. Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase. Science. 2007;315:1726-1729. doi: 10.1126/science.1137503.
19. Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature. 2007;449:496-500. doi: 10.1038/nature06161.
20. Oakhill JS, Chen ZP, Scott JW, Steel R, Castelli LA, Ling N, Macaulay SL, Kemp BE.Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci U S A. 2010;107:19237-19241. doi: 10.1073/pnas.1009705107.
21. Hong SP, Leiper FC, Woods A, Carling D, Carlson M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci U S A. 2003;100:8839-8843. doi: 10.1073/ pnas.1533136100.
22. Sutherland CM, Hawley SA, McCartney RR, Leech A, Stark MJ, Schmidt MC, Hardie DG. Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr Biol. 2003;13:1299-1305.
23. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol. 2003;13:2004-2008.
24. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR, Hardie DG. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003;2:28. doi: 10.1186/1475-4924-2-28.
25. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. The tumor suppressor LKB1 kinase directly activates AMPactivated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004;101:3329-3335. doi: 10.1073/pnas.0308061100.
26. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2:9-19. doi: 10.1016/j.cmet.2005.05.009.
27. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. Ca2+/calmodulin-dependent protein kinase kinasebeta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21-33. doi: 10.1016/j.cmet.2005.06.005.
28. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMPactivated protein kinase kinases. J Biol Chem. 2005;280:29060-29066. doi: 10.1074/jbc.M503824200.
29. Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137-163. doi: 10.1146/annurev. biochem.75.103004.142702.
30. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001;23:1112-1119. doi: 10.1002/ bies.10009.
31. Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013;18:556-566. doi: 10.1016/j.cmet.2013.08.019.
32. Ross FA, Jensen TE, Hardie DG. Differential regulation by AMP and ADP of AMPK complexes containing different subunit isoforms. Biochem J. 2016;473:189-199. doi: 10.1042/BJ20150910.
33. Xiao B, Sanders MJ, Underwood E, et al. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011;472:230-233. doi: 10.1038/ nature09932.
34. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11:554-565. doi: 10.1016/j. cmet.2010.04.001.
35. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMPactivated protein kinase in intact cells Eur J Biochem. 1995;229:558-565.
36. Gómez-Galeno JE, Dang Q, Nguyen TH, et al. A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis. ACS Med Chem Lett. 2010;1:478-482. doi: 10.1021/ml100143q.
37. Langendorf CG, Ngoei KR, Scott JW, Ling NX, Issa SM, Gorman MA, Parker MW, Sakamoto K, Oakhill JS, Kemp BE. Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nat Commun. 2016;7:10912. doi: 10.1038/ncomms10912.
38. Cool B, Zinker B, Chiou W, 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;3:403-416. doi: 10.1016/j.cmet.2006.05.005.
39. Zadra G, Photopoulos C, Tyekucheva S, Heidari P, Weng QP, Fedele G, Liu H, Scaglia N, Priolo C, Sicinska E, Mahmood U, Signoretti S, Birnberg N, Loda M. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol Med. 2014;6:519-538. doi: 10.1002/ emmm.201302734.
40. Salatto CT, Miller RA, Cameron KO, et al. Selective activation of AMPK b1-containing isoforms improves kidney function in a rat model of diabetic nephropathy. J Pharmacol Exp Ther. 2017;361:303-311. doi: 10.1124/ jpet.116.237925.
41. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG. The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012;336:918-922. doi: 10.1126/ science.1215327.
42. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, Allard MF. 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol. 2003;284:R936-R944. doi: 10.1152/ ajpregu.00319.2002.
43. Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes. 1991;40:1259-1266.
44. Gadalla AE, Pearson T, Currie AJ, Dale N, Hawley SA, Sheehan M, Hirst W, Michel AD, Randall A, Hardie DG, Frenguelli BG. AICA riboside both activates AMP-activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus. J Neurochem. 2004;88:1272-1282.
45. Hunter RW, Foretz M, Bultot L, Fullerton MD, Deak M, Ross FA, Hawley SA, Shpiro N, Viollet B, Barron D, Kemp BE, Steinberg GR, Hardie DG, Sakamoto K. Mechanism of action of compound-13: an 1-selective small molecule activator of AMPK. Chem Biol. 2014;21:866-879. doi: 10.1016/j.chembiol.2014.05.014.
46. Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem. 2007;282:32539-32548. doi: 10.1074/jbc.M706543200.
47. Göransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem. 2007;282:32549-32560. doi: 10.1074/jbc.M706536200.
48. Scott JW, Ling N, Issa SM, Dite TA, O'Brien MT, Chen ZP, Galic S, Langendorf CG, Steinberg GR, Kemp BE, Oakhill JS. Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Chem Biol. 2014;21:619-627. doi: 10.1016/j.chembiol.2014.03.006.
49. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408:297-315. doi: 10.1042/ BJ20070797.
50. Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC. AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell. 2013;49:1167-1175. doi: 10.1016/j. molcel.2013.01.035.
51. Chen Q, Xie B, Zhu S, Rong P, Sheng Y, Ducommun S, Chen L, Quan C, Li M, Sakamoto K, MacKintosh C, Chen S, Wang HY. A Tbc1d1 (Ser231Ala)-knockin mutation partially impairs AICAR-but not exerciseinduced muscle glucose uptake in mice. Diabetologia. 2017;60:336-345. doi: 10.1007/s00125-016-4151-9.
52. Zheng D, MacLean PS, Pohnert SC, Knight JB, Olson AL, Winder WW, Dohm GL. Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol (1985). 2001;91:1073-1083.
53. McGee SL, van Denderen BJ, Howlett KF, Mollica J, Schertzer JD, Kemp BE, Hargreaves M. AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase. Diabetes. 2008;57:860-867. doi: 10.2337/db07-0843.
54. Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, Downes M, Evans RM, Montminy M, Shaw RJ. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell. 2011;145:607-621. doi: 10.1016/j. cell.2011.03.043.
55. Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000;10:1247-1255.
56. Marsin AS, Bouzin C, Bertrand L, Hue L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem. 2002;277:30778-30783. doi: 10.1074/jbc.M205213200.
57. Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J. 2004;381:561-579. doi: 10.1042/BJ20040752.
58. O'Neill HM, Lally JS, Galic S, et al. AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia. 2014;57:1693-1702. doi: 10.1007/ s00125-014-3273-1.
59. Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273:E1107-E1112.
60. Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19:1649-1654. doi: 10.1038/ nm.3372.
61. Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol (1985). 2000;88:2219-2226.
62. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A. 2007;104:12017-12022. doi: 10.1073/pnas.0705070104.
63. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009;458:1056-1060. doi: 10.1038/nature07813.
64. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1:361-370. doi: 10.1016/j.cmet.2005.05.004.
65. Sung MM, Zordoky BN, Bujak AL, Lally JS, Fung D, Young ME, Horman S, Miller EJ, Light PE, Kemp BE, Steinberg GR, Dyck JR. AMPK deficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism. Cardiovasc Res. 2015;107:235-245. doi: 10.1093/cvr/cvv166.
66. Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456-461. doi: 10.1126/science.1196371.
67. Wang S, Wang C, Yan F, Wang T, He Y, Li H, Xia Z, Zhang Z. N-Acetylcysteine attenuates diabetic myocardial ischemia reperfusion injury through inhibiting excessive autophagy. Mediators Inflamm. 2017;2017:9257291. doi: 10.1155/2017/9257291.
68. Muoio DM, Seefeld K, Witters LA, Coleman RA. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem J. 1999;338(pt 3):783-791.
69. Hoppe S, Bierhoff H, Cado I, Weber A, Tiebe M, Grummt I, Voit R. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc Natl Acad Sci U S A. 2009;106:17781-17786. doi: 10.1073/ pnas.0909873106.
70. Browne GJ, Finn SG, Proud CG. Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398. J Biol Chem. 2004;279:12220-12231. doi: 10.1074/jbc.M309773200.
71. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577-590.
72. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214-226. doi: 10.1016/j. molcel.2008.03.003.
73. Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD. 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. 1995;270:17513-17520.
74. Coven DL, Hu X, Cong L, Bergeron R, Shulman GI, Hardie DG, Young LH. Physiological role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab. 2003;285:E629-E636. doi: 10.1152/ajpendo.00171.2003.
75. Russell RR 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest. 2004;114:495-503. doi: 10.1172/JCI19297.
76. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007;100:914-922. doi: 10.1161/01. RES.0000261924.76669.36.
77. Sakamoto K, Zarrinpashneh E, Budas GR, Pouleur AC, Dutta A, Prescott AR, Vanoverschelde JL, Ashworth A, Jovanovi A, Alessi DR, Bertrand L. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha1. Am J Physiol Endocrinol Metab. 2006;290:E780-E788. doi: 10.1152/ajpendo.00443.2005.
78. Zarrinpashneh E, Carjaval K, Beauloye C, Ginion A, Mateo P, Pouleur AC, Horman S, Vaulont S, Hoerter J, Viollet B, Hue L, Vanoverschelde JL, Bertrand L. Role of the alpha2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia. Am J Physiol Heart Circ Physiol. 2006;291:H2875-H2883. doi: 10.1152/ ajpheart.01032.2005.
79. Zarrinpashneh E, Beauloye C, Ginion A, Pouleur AC, Havaux X, Hue L, Viollet B, Vanoverschelde JL, Bertrand L. AMPKalpha2 counteracts the development of cardiac hypertrophy induced by isoproterenol. Biochem Biophys Res Commun. 2008;376:677-681. doi: 10.1016/j. bbrc.2008.09.057.
80. Gollob MH, Green MS, Tang AS, Gollob T, Karibe A, Ali Hassan AS, Ahmad F, Lozado R, Shah G, Fananapazir L, Bachinski LL, Roberts R, Hassan AS. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344:1823-1831. doi: 10.1056/NEJM200106143442403.
81. Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, Seidman CE. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest. 2002;109:357-362. doi: 10.1172/ JCI14571.
82. Charron P, Genest M, Richard P, Komajda M, Pochmalicki G. A familial form of conduction defect related to a mutation in the PRKAG2 gene. Europace. 2007;9:597-600. doi: 10.1093/europace/eum071.
83. Thevenon J, Laurent G, Ader F, et al. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace. 2016:pii: euw067. [Epub ahead of print]. doi: 10.1093/europace/euw067.
84. Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H. Mutations in the gamma(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. 2001;10:1215-1220.
85. Akman HO, Sampayo JN, Ross FA, Scott JW, Wilson G, Benson L, Bruno C, Shanske S, Hardie DG, Dimauro S. Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase. Pediatr Res. 2007;62:499-504. doi: 10.1203/PDR.0b013e3181462b86.
86. Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez-Atayde AR, Spirito P, Wright GB, Kanter RJ, Seidman CE, Seidman JG. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005;352:362-372. doi: 10.1056/NEJMoa033349.
87. Bayrak F, Komurcu-Bayrak E, Mutlu B, Kahveci G, Basaran Y, Erginel-Unaltuna N. Ventricular pre-excitation and cardiac hypertrophy mimicking hypertrophic cardiomyopathy in a Turkish family with a novel PRKAG2 mutation. Eur J Heart Fail. 2006;8:712-715. doi: 10.1016/j. ejheart.2006.03.006.
88. Xie C, Zhang YP, Song L, et al. Genome editing with CRISPR/Cas9 in postnatal mice corrects PRKAG2 cardiac syndrome. Cell Res. 2016;26:1099-1111. doi: 10.1038/cr.2016.101.
89. Gollob MH, Seger JJ, Gollob TN, Tapscott T, Gonzales O, Bachinski L, Roberts R. Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy. Circulation. 2001;104:3030-3033.
90. Burwinkel B, Scott JW, Bührer C, van Landeghem FK, Cox GF, Wilson CJ, Grahame Hardie D, Kilimann MW. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet. 2005;76:1034-1049. doi: 10.1086/430840.
91. Lafor?t P, Richard P, Said MA, Romero NB, Lacene E, Leroy JP, Baussan C, Hogrel JY, Lavergne T, Wahbi K, Hainque B, Duboc D. A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Neuromuscul Disord. 2006;16:178-182. doi: 10.1016/j.nmd.2005.12.004.
92. Daniel T, Carling D. Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome. J Biol Chem. 2002;277:51017-51024. doi: 10.1074/jbc.M207093200.
93. Cheung PC, Salt IP, Davies SP, Hardie DG, Carling D. Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J. 2000;346(pt 3):659-669.
94. Luptak I, Shen M, He H, Hirshman MF, Musi N, Goodyear LJ, Yan J, Wakimoto H, Morita H, Arad M, Seidman CE, Seidman JG, Ingwall JS, Balschi JA, Tian R. Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J Clin Invest. 2007;117:1432-1439. doi: 10.1172/JCI30658.
95. Kim M, Hunter RW, Garcia-Menendez L, Gong G, Yang YY, Kolwicz SC Jr, Xu J, Sakamoto K, Wang W, Tian R. Mutation in the 2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circ Res. 2014;114:966-975. doi: 10.1161/CIRCRESAHA.114.302364.
96. Dalle Pezze P, Ruf S, Sonntag AG, et al. A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Nat Commun. 2016;7:13254. doi: 10.1038/ncomms13254.
97. Arad M, Moskowitz IP, Patel VV, et al. Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy. Circulation. 2003;107:2850-2856. doi: 10.1161/01.CIR.0000075270.13497.2B.
98. Yavari A, Stocker CJ, Ghaffari S, et al. Chronic Activation of 2 AMPK Induces Obesity and Reduces Cell Function. Cell Metab. 2016;23:821-836. doi: 10.1016/j.cmet.2016.04.003.
99. Yang X, Mudgett J, Bou-About G, et al. Physiological expression of AMPK2RG mutation causes Wolff-Parkinson-White syndrome and induces kidney injury in mice. J Biol Chem. 2016;291:23428-23439. doi: 10.1074/jbc.M116.738591.
100. Yang Y, Atasoy D, Su HH, Sternson SM. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell. 2011;146:992-1003. doi: 10.1016/j.cell.2011.07.039.
101. Andersson U, Filipsson K, Abbott CR, Woods A, Smith K, Bloom SR, Carling D, Small CJ. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. 2004;279:12005-12008. doi: 10.1074/jbc.C300557200.
102. Milan D, Jeon JT, Looft C, et al. A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science. 2000;288:1248-1251.
103. Costford SR, Kavaslar N, Ahituv N, Chaudhry SN, Schackwitz WS, Dent R, Pennacchio LA, McPherson R, Harper ME. Gain-of-function R225W mutation in human AMPKgamma(3) causing increased glycogen and decreased triglyceride in skeletal muscle. PLoS One. 2007;2:e903. doi: 10.1371/journal.pone.0000903.
104. Crawford SA, Costford SR, Aguer C, Thomas SC, deKemp RA, DaSilva JN, Lafontaine D, Kendall M, Dent R, Beanlands RS, McPherson R, Harper ME. Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)gamma(3) results in increased oxidative capacity and glucose uptake in human primary myotubes. Diabetologia. 2010;53:1986-1997. doi: 10.1007/s00125-010-1788-7.
105. Morrow VA, Foufelle F, Connell JM, Petrie JR, Gould GW, Salt IP. Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J Biol Chem. 2003;278:31629-31639. doi: 10.1074/jbc.M212831200.
106. Stahmann N, Woods A, Spengler K, Heslegrave A, Bauer R, Krause S, Viollet B, Carling D, Heller R. Activation of AMP-activated protein kinase by vascular endothelial growth factor mediates endothelial angiogenesis independently of nitric-oxide synthase. J Biol Chem. 2010;285:10638-10652. doi: 10.1074/jbc.M110.108688.
107. Dong Y, Zhang M, Liang B, Xie Z, Zhao Z, Asfa S, Choi HC, Zou MH. Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation. 2010;121:792-803. doi: 10.1161/CIRCULATIONAHA.109.900928.
108. Bess E, Fisslthaler B, Frömel T, Fleming I. Nitric oxide-induced activation of the AMP-activated protein kinase 2 subunit attenuates IB kinase activity and inflammatory responses in endothelial cells. PLoS One. 2011;6:e20848. doi: 10.1371/journal.pone.0020848.
109. Wang S, Zhang M, Liang B, Xu J, Xie Z, Liu C, Viollet B, Yan D, Zou MH. AMPK{alpha}2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo. Role of 26S proteasomes. Circ Res. 2010;106:1117-1128. doi: 10.1161/ CIRCRESAHA.109.212530.
110. Nagata D, Mogi M, Walsh K. AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem. 2003;278:31000-31006. doi: 10.1074/jbc. M300643200.
111. Wang J, Alexanian A, Ying R, Kizhakekuttu TJ, Dharmashankar K, Vasquez-Vivar J, Gutterman DD, Widlansky ME. Acute exposure to low glucose rapidly induces endothelial dysfunction and mitochondrial oxidative stress: role for AMP kinase. Arterioscler Thromb Vasc Biol. 2012;32:712-720. doi: 10.1161/ATVBAHA.111.227389.
112. Fleming I, Fisslthaler B, Dixit M, Busse R. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci. 2005;118:4103-4111. doi: 10.1242/jcs.02541.
113. Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem. 2004;279:1304-1309. doi: 10.1074/ jbc.M310389200.
114. Day RM, Lee YH, Han L, Kim YC, Feng YH. Angiotensin II activates AMPK for execution of apoptosis through energy-dependent and-independent mechanisms. Am J Physiol Lung Cell Mol Physiol. 2011;301:L772-L781. doi: 10.1152/ajplung.00072.2011.
115. Xu X, Jhun BS, Ha CH, Jin ZG. Molecular mechanisms of ghrelinmediated endothelial nitric oxide synthase activation. Endocrinology. 2008;149:4183-4192. doi: 10.1210/en.2008-0255.
116. Stahmann N, Woods A, Carling D, Heller R. Thrombin activates AMPactivated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol Cell Biol. 2006;26:5933-5945. doi: 10.1128/MCB.00383-06.
117. Levine YC, Li GK, Michel T. Agonist-modulated regulation of AMPactivated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK-> Rac1-> Akt-> endothelial nitric-oxide synthase pathway. J Biol Chem. 2007;282:20351-20364. doi: 10.1074/jbc.M702182200.
118. Mount PF, Lane N, Venkatesan S, Steinberg GR, Fraser SA, Kemp BE, Power DA. Bradykinin stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK. Atherosclerosis. 2008;200:28-36. doi: 10.1016/j.atherosclerosis.2007.12.003.
119. Yang S, Wang J. Estrogen activates AMP-activated protein kinase in human endothelial cells via ER/Ca(2+)/calmodulin-dependent protein kinase kinase pathway. Cell Biochem Biophys. 2015;72:701-707. doi: 10.1007/s12013-015-0521-z.
120. Reihill JA, Ewart MA, Salt IP. The role of AMP-activated protein kinase in the functional effects of vascular endothelial growth factor-A and-B in human aortic endothelial cells. Vasc Cell. 2011;3:9. doi: 10.1186/2045-824X-3-9.
121. Ceolotto G, Gallo A, Papparella I, Franco L, Murphy E, Iori E, Pagnin E, Fadini GP, Albiero M, Semplicini A, Avogaro A. Rosiglitazone reduces glucose-induced oxidative stress mediated by NAD(P)H oxidase via AMPK-dependent mechanism. Arterioscler Thromb Vasc Biol. 2007;27:2627-2633. doi: 10.1161/ATVBAHA.107.155762.
122. Rutherford C, Speirs C, Williams JJ, Ewart MA, Mancini SJ, Hawley SA, Delles C, Viollet B, Costa-Pereira AP, Baillie GS, Salt IP, Palmer TM. Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Sci Signal. 2016;9:ra109. doi: 10.1126/scisignal.aaf8566.
123. Hwang HJ, Chung HS, Jung TW, Ryu JY, Hong HC, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH, Yoo HJ. The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt-and AMPK-dependent mechanisms. Mol Cell Endocrinol. 2015;405:25-34. doi: 10.1016/j. mce.2015.01.025.
124. Krasner NM, Ido Y, Ruderman NB, Cacicedo JM. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One. 2014;9:e97554. doi: 10.1371/journal.pone.0097554.
125. Sun W, Lee TS, Zhu M, Gu C, Wang Y, Zhu Y, Shyy JY. Statins activate AMP-activated protein kinase in vitro and in vivo. Circulation. 2006;114:2655-2662. doi: 10.1161/CIRCULATIONAHA.106.630194.
126. Murakami H, Murakami R, Kambe F, Cao X, Takahashi R, Asai T, Hirai T, Numaguchi Y, Okumura K, Seo H, Murohara T. Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. Biochem Biophys Res Commun. 2006;341:973-978. doi: 10.1016/j. bbrc.2006.01.052.
127. Wu Y, Song P, Xu J, Zhang M, Zou MH. Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem. 2007;282:9777-9788. doi: 10.1074/jbc.M608310200.
128. Weikel KA, Cacicedo JM, Ruderman NB, Ido Y. Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells. Am J Physiol Cell Physiol. 2015;308:C249-C263. doi: 10.1152/ ajpcell.00265.2014.
129. Cacicedo JM, Yagihashi N, Keaney JF Jr, Ruderman NB, Ido Y. AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2004;324:1204-1209. doi: 10.1016/j. bbrc.2004.09.177.
130. Heathcote HR, Mancini SJ, Strembitska A, Jamal K, Reihill JA, Palmer TM, Gould GW, Salt IP. Protein kinase C phosphorylates AMP-activated protein kinase 1 Ser487. Biochem J. 2016;473:4681-4697. doi: 10.1042/BCJ20160211.
131. Dagher Z, Ruderman N, Tornheim K, Ido Y. The effect of AMP-activated protein kinase and its activator AICAR on the metabolism of human umbilical vein endothelial cells. Biochem Biophys Res Commun. 1999;265:112-115. doi: 10.1006/bbrc.1999.1635.
132. Ido Y, Carling D, Ruderman N. Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes. 2002;51:159-167.
133. Goirand F, Solar M, Athea Y, Viollet B, Mateo P, Fortin D, Leclerc J, Hoerter J, Ventura-Clapier R, Garnier A. Activation of AMP kinase alpha1 subunit induces aortic vasorelaxation in mice. J Physiol. 2007;581:1163-1171. doi: 10.1113/jphysiol.2007.132589.
134. Song P, Wang S, He C, Wang S, Liang B, Viollet B, Zou MH. AMPK2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circ Res. 2011;109:1230-1239. doi: 10.1161/ CIRCRESAHA.111.250423.
135. Motobayashi Y, Izawa-Ishizawa Y, Ishizawa K, Orino S, Yamaguchi K, Kawazoe K, Hamano S, Tsuchiya K, Tomita S, Tamaki T. Adiponectin inhibits insulin-like growth factor-1-induced cell migration by the suppression of extracellular signal-regulated kinase . activation, but not Akt in vascular smooth muscle cells. Hypertens Res. 2009;32:188-193. doi: 10.1038/hr.2008.19.
136. Ning J, Clemmons DR. AMP-activated protein kinase inhibits IGF-I signaling and protein synthesis in vascular smooth muscle cells via stimulation of insulin receptor substrate 1 S794 and tuberous sclerosis 2 S1345 phosphorylation. Mol Endocrinol. 2010;24:1218-1229. doi: 10.1210/ me.2009-0474.
137. Gayard M, Guilluy C, Rousselle A, Viollet B, Henrion D, Pacaud P, Loirand G, Rolli-Derkinderen M. AMPK alpha 1-induced RhoA phosphorylation mediates vasoprotective effect of estradiol. Arterioscler Thromb Vasc Biol. 2011;31:2634-2642. doi: 10.1161/ATVBAHA.111.228304.
138. Pyla R, Pichavaram P, Fairaq A, Park MA, Kozak M, Kamath V, Patel VS, Segar L. Altered energy state reversibly controls smooth muscle contractile function in human saphenous vein during acute hypoxiareoxygenation: Role of glycogen, AMP-activated protein kinase, and insulin-independent glucose uptake. Biochem Pharmacol. 2015;97:77-88. doi: 10.1016/j.bcp.2015.06.036.
139. Nagata D, Takeda R, Sata M, Satonaka H, Suzuki E, Nagano T, Hirata Y. AMP-activated protein kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation. Circulation. 2004;110:444-451. doi: 10.1161/01.CIR.0000136025.96811.76.
140. Kim JE, Choi HC. Losartan inhibits vascular smooth muscle cell proliferation through activation of AMP-activated protein kinase. Korean J Physiol Pharmacol. 2010;14:299-304. doi: 10.4196/ kjpp.2010.14.5.299.
141. Ning J, Xi G, Clemmons DR. Suppression of AMPK activation via S485 phosphorylation by IGF-I during hyperglycemia is mediated by AKT activation in vascular smooth muscle cells. Endocrinology. 2011;152:3143-3154. doi: 10.1210/en.2011-0155.
142. Son BK, Akishita M, Iijima K, Kozaki K, Maemura K, Eto M, Ouchi Y. Adiponectin antagonizes stimulatory effect of tumor necrosis factoralpha on vascular smooth muscle cell calcification: regulation of growth arrest-specific gene 6-mediated survival pathway by adenosine 5'-monophosphate-activated protein kinase. Endocrinology. 2008;149:1646-1653. doi: 10.1210/en.2007-1021.
143. Cao X, Li H, Tao H, Wu N, Yu L, Zhang D, Lu X, Zhu J, Lu Z, Zhu Q. Metformin inhibits vascular calcification in female rat aortic smooth muscle cells via the AMPK-eNOS-NO pathway. Endocrinology. 2013;154:3680-3689. doi: 10.1210/en.2013-1002.
144. Siragusa M, Fleming I. The eNOS signalosome and its link to endothelial dysfunction. Pflugers Arch. 2016;468:1125-1137. doi: 10.1007/ s00424-016-1839-0.
145. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, Power DA, Ortiz de Montellano PR, Kemp BE. AMPactivated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999;443:285-289.
146. Chen Z, Peng IC, Sun W, Su MI, Hsu PH, Fu Y, Zhu Y, DeFea K, Pan S, Tsai MD, Shyy JY. AMP-activated protein kinase functionally phosphorylates endothelial nitric oxide synthase Ser633. Circ Res. 2009;104:496-505. doi: 10.1161/CIRCRESAHA.108.187567.
147. Wang S, Xu J, Song P, Viollet B, Zou MH. In vivo activation of AMPactivated protein kinase attenuates diabetes-enhanced degradation of GTP cyclohydrolase I. Diabetes. 2009;58:1893-1901. doi: 10.2337/ db09-0267.
148. Mount PF, Hill RE, Fraser SA, Levidiotis V, Katsis F, Kemp BE, Power DA. Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177. Am J Physiol Renal Physiol. 2005;289:F1103-F1115. doi: 10.1152/ajprenal.00458.2004.
149. Kukidome D, Nishikawa T, Sonoda K, Imoto K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Matsumura T, Araki E. 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. 2006;55:120-127.
150. Shah MS, Brownlee M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res. 2016;118:1808-1829. doi: 10.1161/CIRCRESAHA.116.306923.
151. Colombo SL, Moncada S. AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. Biochem J. 2009;421:163-169. doi: 10.1042/BJ20090613.
152. Hou X, Song J, Li XN, Zhang L, Wang X, Chen L, Shen YH. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010;396:199-205. doi: 10.1016/j. bbrc.2010.04.017.
153. Dong Y, Zhang M, Wang S, Liang B, Zhao Z, Liu C, Wu M, Choi HC, Lyons TJ, Zou MH. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes. 2010;59:1386-1396. doi: 10.2337/db09-1637.
154. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J. 2014;35:1782-1791. doi: 10.1093/eurheartj/ ehu203.
155. Salt IP, Palmer TM. Exploiting the anti-inflammatory effects of AMPactivated protein kinase activation. Expert Opin Investig Drugs. 2012;21:1155-1167. doi: 10.1517/13543784.2012.696609.
156. Ewart MA, Kohlhaas CF, Salt IP. Inhibition of tumor necrosis factor alpha-stimulated monocyte adhesion to human aortic endothelial cells by AMP-activated protein kinase. Arterioscler Thromb Vasc Biol. 2008;28:2255-2257. doi: 10.1161/ATVBAHA.108.175919.
157. Spiecker M, Peng HB, Liao JK. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha. J Biol Chem. 1997;272:30969-30974.
158. Zhang Y, Qiu J, Wang X, Zhang Y, Xia M. AMP-activated protein kinase suppresses endothelial cell inflammation through phosphorylation of transcriptional coactivator p300. Arterioscler Thromb Vasc Biol. 2011;31:2897-2908. doi: 10.1161/ATVBAHA.111.237453.
159. Schulz E, Dopheide J, Schuhmacher S, Thomas SR, Chen K, Daiber A, Wenzel P, Münzel T, Keaney JF Jr. Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation. 2008;118:1347-1357. doi: 10.1161/ CIRCULATIONAHA.108.784298.
160. Mancini SJ, White AD, Bijland S, Rutherford C, Graham D, Richter EA, Viollet B, Touyz RM, Palmer TM, Salt IP. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation. Mol Cell Endocrinol. 2017;440:44-56. doi: 10.1016/j.mce.2016.11.010.
161. Kim SA, Choi HC. Metformin inhibits inflammatory response via AMPKPTEN pathway in vascular smooth muscle cells. Biochem Biophys Res Commun. 2012;425:866-872. doi: 10.1016/j.bbrc.2012.07.165.
162. He C, Li H, Viollet B, Zou MH, Xie Z. AMPK suppresses vascular inflammation in vivo by inhibiting signal transducer and activator of transcription-1. Diabetes. 2015;64:4285-4297. doi: 10.2337/db15-0107.
163. Zippel N, Malik RA, Frömel T, Popp R, Bess E, Strilic B, Wettschureck N, Fleming I, Fisslthaler B. Transforming growth factor-activated kinase 1 regulates angiogenesis via AMP-activated protein kinase-1 and redox balance in endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:2792-2799. doi: 10.1161/ATVBAHA.113.301848.
164. Xu MJ, Song P, Shirwany N, Liang B, Xing J, Viollet B, Wang X, Zhu Y, Zou MH. Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase subunits. Arterioscler Thromb Vasc Biol. 2011;31:1757-1765. doi: 10.1161/ATVBAHA.111.227991.
165. Ouchi N, Shibata R, Walsh K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ Res. 2005;96:838-846. doi: 10.1161/01.RES.0000163633.10240.3b.
166. Wang S, Liang B, Viollet B, Zou MH. Inhibition of the AMP-activated protein kinase-2 accentuates agonist-induced vascular smooth muscle contraction and high blood pressure in mice. Hypertension. 2011;57:1010-1017. doi: 10.1161/HYPERTENSIONAHA.110.168906.
167. Schneider H, Schubert KM, Blodow S, Kreutz CP, Erdogmus S, Wiedenmann M, Qiu J, Fey T, Ruth P, Lubomirov LT, Pfitzer G, Mederos Y Schnitzler M, Hardie DG, Gudermann T, Pohl U. AMPK dilates resistance arteries via activation of SERCA and BKCa channels in smooth muscle. Hypertension. 2015;66:108-116. doi: 10.1161/ HYPERTENSIONAHA.115.05514.
168. Igata M, Motoshima H, Tsuruzoe K, Kojima K, Matsumura T, Kondo T, Taguchi T, Nakamaru K, Yano M, Kukidome D, Matsumoto K, Toyonaga T, Asano T, Nishikawa T, Araki E. Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ Res. 2005;97:837-844. doi: 10.1161/01.RES.0000185823.73556.06.
169. Ding Y, Zhang M, Zhang W, Lu Q, Cai Z, Song P, Okon IS, Xiao L, Zou MH. AMP-activated protein kinase alpha 2 deletion induces VSMC phenotypic switching and reduces features of atherosclerotic plaque stability. Circ Res. 2016;119:718-730. doi: 10.1161/CIRCRESAHA.116.308689.
170. Song P, Zhou Y, Coughlan KA, Dai X, Xu H, Viollet B, Zou MH. Adenosine monophosphate-activated protein kinase-2 deficiency promotes vascular smooth muscle cell migration via S-phase kinaseassociated protein 2 upregulation and E-cadherin downregulation. Arterioscler Thromb Vasc Biol. 2013;33:2800-2809. doi: 10.1161/ ATVBAHA.113.301869.
171. Cai Z, Ding Y, Zhang M, Lu Q, Wu S, Zhu H, Song P, Zou MH. Ablation of adenosine monophosphate-activated protein kinase 1 in vascular smooth muscle cells promotes diet-induced atherosclerotic calcification in vivo. Circ Res. 2016;119:422-433. doi: 10.1161/ CIRCRESAHA.116.308301.
172. Cacicedo JM, Gauthier MS, Lebrasseur NK, Jasuja R, Ruderman NB, Ido Y. Acute exercise activates AMPK and eNOS in the mouse aorta. Am J Physiol Heart Circ Physiol. 2011;301:H1255-H1265. doi: 10.1152/ ajpheart.01279.2010.
173. Ma L, Ma S, He H, Yang D, Chen X, Luo Z, Liu D, Zhu Z. Perivascular fat-mediated vascular dysfunction and remodeling through the AMPK/ mTOR pathway in high-fat diet-induced obese rats. Hypertens Res. 2010;33:446-453. doi: 10.1038/hr.2010.11.
174. Zhao CX, Xu X, Cui Y, Wang P, Wei X, Yang S, Edin ML, Zeldin DC, Wang DW. Increased endothelial nitric-oxide synthase expression reduces hypertension and hyperinsulinemia in fructose-treated rats. J Pharmacol Exp Ther. 2009;328:610-620. doi: 10.1124/jpet.108.143396.
175. Bradley EA, Eringa EC, Stehouwer CD, Korstjens I, van Nieuw Amerongen GP, Musters R, Sipkema P, Clark MG, Rattigan S. 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. 2010;30:1137-1142. doi: 10.1161/ATVBAHA.110.204404.
176. Ford RJ, Teschke SR, Reid EB, Durham KK, Kroetsch JT, Rush JW. AMP-activated protein kinase activator AICAR acutely lowers blood pressure and relaxes isolated resistance arteries of hypertensive rats. J Hypertens. 2012;30:725-733. doi: 10.1097/HJH.0b013e32835050ca.
177. Ford RJ, Rush JW. Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent. Am J Physiol Heart Circ Physiol. 2011;300:H64-H75. doi: 10.1152/ajpheart.00597.2010.
178. Bosselaar M, Boon H, van Loon LJ, van den Broek PH, Smits P, Tack CJ. Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle. Am J Physiol Endocrinol Metab. 2009;297:E759-E766. doi: 10.1152/ajpendo.00141.2009.
179. Enkhjargal B, Godo S, Sawada A, Suvd N, Saito H, Noda K, Satoh K, Shimokawa H. Endothelial AMP-activated protein kinase regulates blood pressure and coronary flow responses through hyperpolarization mechanism in mice. Arterioscler Thromb Vasc Biol. 2014;34:1505-1513. doi: 10.1161/ATVBAHA.114.303735.
180. Liang B, Wang S, Wang Q, Zhang W, Viollet B, Zhu Y, Zou MH. Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-2 in vivo. Arterioscler Thromb Vasc Biol. 2013;33:595-604. doi: 10.1161/ATVBAHA.112.300606.
181. Kohlstedt K, Trouvain C, Boettger T, Shi L, Fisslthaler B, Fleming I. AMP-activated protein kinase regulates endothelial cell angiotensinconverting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143/145. Circ Res. 2013;112:1150-1158. doi: 10.1161/CIRCRESAHA.113.301282.
182. Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, Pedersen O, Schmitz O, Lund S. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes. 2002;51:2199-2206.
183. Meijer RI, Bakker W, Alta CL, Sipkema P, Yudkin JS, Viollet B, Richter EA, Smulders YM, van Hinsbergh VW, Serné EH, Eringa EC. Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice. Diabetes. 2013;62:590-598. doi: 10.2337/db11-1603.
184. Almabrouk TA, Ugusman AB, Katwan OJ, Salt IP, Kennedy S. Deletion of AMPK1 attenuates the anticontractile effect of perivascular adipose tissue (PVAT) and reduces adiponectin release [published online ahead of print September 26, 2016]. Br J Pharmacol. doi: 10.1111/bph.13633. http://onlinelibrary.wiley.com/doi/10.1111/bph.13633/abstract.
185. Gaskin FS, Kamada K, Zuidema MY, Jones AW, Rubin LJ, Korthuis RJ. Isoform-selective 5'-AMP-activated protein kinase-dependent preconditioning mechanisms to prevent postischemic leukocyte-endothelial cell adhesive interactions. Am J Physiol Heart Circ Physiol. 2011;300:H1352-H1360. doi: 10.1152/ajpheart.00944.2010.
186. Li D, Wang D, Wang Y, Ling W, Feng X, Xia M. Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice. J Biol Chem. 2010;285:33499-33509. doi: 10.1074/ jbc.M110.159772.
187. Chen B, Li J, Zhu H. AMP-activated protein kinase attenuates oxLDL uptake in macrophages through PP2A/NF-B/LOX-1 pathway. Vascul Pharmacol. 2016;85:1-10. doi: 10.1016/j.vph.2015.08.012.
188. Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64:2028-2041. doi: 10.2337/db14-1225.
189. Wang Q, Zhang M, Liang B, Shirwany N, Zhu Y, Zou MH. Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS One. 2011;6:e25436. doi: 10.1371/journal.pone.0025436.
190. 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. 1998;352:854-865.
191. Dai X, Ding Y, Liu Z, Zhang W, Zou MH. Phosphorylation of CHOP (C/EBP Homologous Protein) by the AMP-activated protein kinase alpha 1 in macrophages promotes CHOP degradation and reduces injuryinduced neointimal disruption in vivo. Circ Res. 2016;119:1089-1100. doi: 10.1161/CIRCRESAHA.116.309463.
192. Li FY, Lam KS, Tse HF, Chen C, Wang Y, Vanhoutte PM, Xu A. Endothelium-selective activation of AMP-activated protein kinase prevents diabetes mellitus-induced impairment in vascular function and reendothelialization via induction of heme oxygenase-1 in mice. Circulation. 2012;126:1267-1277. doi: 10.1161/CIRCULATIONAHA.112.108159.
193. Cao Q, Cui X, Wu R, Zha L, Wang X, Parks JS, Yu L, Shi H, Xue B. Myeloid deletion of 1AMPK exacerbates atherosclerosis in LDL receptor knockout (LDLRKO) mice. Diabetes. 2016;65:1565-1576. doi: 10.2337/db15-0917.
194. Song Y, Wu Y, Su X, Zhu Y, Liu L, Pan Y, Zhu B, Yang L, Gao L, Li M. Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms. Pharmacol Res. 2016;107:117-124. doi: 10.1016/j.phrs.2016.03.010.
195. Dean A, Nilsen M, Loughlin L, Salt IP, MacLean MR. Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension. 2016;68:446-454. doi: 10.1161/ HYPERTENSIONAHA.116.07353.
196. Omura J, Satoh K, Kikuchi N, et al. Protective roles of endothelial AMP-activated protein kinase against hypoxia-induced pulmonary hypertension in mice. Circ Res. 2016;119:197-209. doi: 10.1161/ CIRCRESAHA.115.308178.
197. Ibe JC, Zhou Q, Chen T, Tang H, Yuan JX, Raj JU, Zhou G. Adenosine monophosphate-activated protein kinase is required for pulmonary artery smooth muscle cell survival and the development of hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol. 2013;49:609-618. doi: 10.1165/rcmb.2012-0446OC.
198. Moral-Sanz J, Mahmoud AD, Ross FA, Eldstrom J, Fedida D, Hardie DG, Evans AM. AMP-activated protein kinase inhibits Kv 1.5 channel currents of pulmonary arterial myocytes in response to hypoxia and inhibition of mitochondrial oxidative phosphorylation. J Physiol. 2016;594:4901-4915. doi: 10.1113/JP272032.