Mitochondria in the diabetic heart

Cardiovascular Research

Volumn 88, Issue 2, 2010, Pages 229-240

  Bugger, Heiko ^a   Abel, E Dale ^b  

^a UNIVERSITY OF FREIBURG   (Germany)

^b UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

Diabetes; Heart; Metabolism; Mitochondria

Indexed keywords

ADENOSINE TRIPHOSPHATE; INSULIN; PROTEOME; REACTIVE OXYGEN METABOLITE; UNCOUPLING PROTEIN 3;

BIOGENESIS; CALCIUM TRANSPORT; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DISEASE ASSOCIATION; ENERGY METABOLISM; FATTY ACID OXIDATION; HEART CONTRACTION; HEART MITOCHONDRION; HEART MUSCLE CELL; HEART VENTRICLE REMODELING; HUMAN; MYOCARDIAL DISEASE; NONHUMAN; OXIDATIVE PHOSPHORYLATION UNCOUPLING; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN PROCESSING; REVIEW;

ANIMALS; CALCIUM; DIABETES COMPLICATIONS; ENERGY METABOLISM; HEART DISEASES; HUMANS; INSULIN; MITOCHONDRIA, HEART; MITOCHONDRIAL PROTEINS; MYOCARDIUM; OXIDATIVE STRESS; PROTEIN PROCESSING, POST-TRANSLATIONAL; RISK FACTORS; SIGNAL TRANSDUCTION;

EID: 77956572071     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvq239     Document Type: Review

References (131)

1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type ofcardiomyopathy associated with diabetic glomerulosclerosis.Am J Cardiol1972;30: 595-602.
2. Hamby RI, Zoneraich S, Sherman L. Diabetic cardiomyopathy. J Am A 1974;229: 1749-1754.
3. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 1977;60:884-899.
4. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Fra-mingham study. J Am Coll Cardiol 1993;22:6A-13A
5. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. J Am A 1979;241:2035-2038.
6. Bell DS. Diabetic cardiomyopathy. Diabetes Care 2003;26:2949-2951.
7. Fein FS. Diabetic cardiomyopathy. Diabetes Care 1990;13:1169-1179.
8. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z et al. Effect of obesity and insulin resistance on myocardial sub-strate metabolism and efficiency in young women. Circulation 2004;109:2191-2196.
9. DiAm Ant M, Lamb HJ, Groeneveld Y, Endert EL, SmitJW, Bax JJ et al. Diastolic dys-function is associated with altered myocardial metabolism in asymptomatic normo-tensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003; 42:328-335.
10. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 2003;107:3040-3046.
11. CasademontJ, Miro O. Electron transport chain defects in heart failure. Heart Fail Rev 2002;7:131-139.
12. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated car-diomyopathy. Circulation 1997;96:2190-2196.
13. Neubauer S, Krahe T, Schindler R, Horn M, Hillenbrand H, Entzeroth C et al. P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992;86:1810-1818.
14. Rijzewijk LJ, van der Meer RW, Lamb HJ, deJong HW, Lubberink M, Romijn JA et al. Altered myocardial substrate metabolism and decreased diastolic function in nonis-chemic human diabetic cardiomyopathy: studieswith cardiac positron emission tom-ography and magnetic resonance imaging. J Am Coll Cardiol 2009;54:1524-1532.
15. van der Meer RW, Rijzewijk LJ, deJong HW, Lamb HJ, Lubberink M, Romijn JA et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 2009;119:2069-2077.
16. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 2009;54:1891-1898.
17. Bugger H, Abel ED. Rodent models of diabetic cardiomyopathy. Dis Model Mech 2009;2:454-466.
18. Kuo TH, Giacomelli F, WienerJ. Oxidative metabolism of Polytron versus Nagarse mitochondria in hearts ofgenetically diabetic mice. Biochim Biophys Acta 1985;806: 9-15.
19. Kuo TH, Moore KH, Giacomelli F, WienerJ. Defective oxidative metabolism ofheart mitochondria from genetically diabetic mice. Diabetes 1983;32:781-787.
20. Boudina S, Sena S, O'Neill BT, Tathireddy P, Young ME, Abel ED. Reduced mito-chondrial oxidative capacity and increased mitochondrial uncoupling impair myocar-dial energetics in obesity. Circulation 2005;112:2686-2695.
21. Duncan JG, FongJL, Medeiros DM, Finck BN, Kelly DP. Insulin-resistant heart exhi-bits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation 2007; 115:909-917.
22. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX et al. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 2007;56: 2457-2466.
23. Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA et al. Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 2008;57: 2924-2932.
24. Bugger H, Chen D, Riehle C, Soto J, Theobald HA, Hu XX et al. Tissue-specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice. Diabetes 2009;58:1986-1997.
25. Flarsheim CE, Grupp IL, Matlib MA. Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart. Am J Physiol 1996;271:H192-H202.
26. Lashin OM, Szweda PA, Szweda LI, Romani AM. Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. Free Radic Biol Med 2006;40: 886-896.
27. Shen X, Zheng S, Thongboonkerd V, Xu M, Pierce WM Jr, Klein JB et al. Cardiac mitochondrial dAm Age and biogenesis in a chronic model oftype 1 diabetes. Am J Physiol Endocrinol Metab 2004;287:E896-E905.
28. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun U et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hypergly-cemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 2005;146:5341-5349.
29. Mazumder PK, O'Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC et al. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 2004;53:2366-2374.
30. Wang P, Lloyd SG, Zeng H, Bonen A, ChathAm JC. Impact ofaltered substrate util-ization on cardiac function in isolated hearts from Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol 2005;288:H2102-H2110.
31. AoyAm A T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T et al. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the per-oxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 1998;273: 5678-5684.
32. Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 2000;10:238-245.
33. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 2002;109:121-130.
34. Young ME, Patil S, YingJ, Depre C, Ahuja HS, Shipley GL et al. Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J 2001;15:833-845.
35. KjekshusJK, Mjos OD. Effect offree fatty acids on myocardial function and metab-olism in the ischemic dog heart. J Clin Invest 1972;51:1767-1776.
36. Mjos OD. Effect offree fatty acids on myocardial function and oxygen consumption in intact dogs. J Clin Invest 1971;50:1386-1389.
37. How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS. Increased myo-cardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006;55:466-473.
38. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 2002;51:2587-2595.
39. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S et al. mitochondrial superoxide: production, biological effects, and activation of uncoupling pro-teins. Free Radic Biol Med 2004;37:755-767.
40. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling pro-teins UCP2 and UCP3. Cell Metab 2005;2:85-93.
41. Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol Rev 1984;64: 1-64.
42. Ledesma A, de Lacoba MG, Rial E. The mitochondrial uncoupling proteins. Genome Biol 2002;3:Reviews3015.
43. Murray AJ, Anderson RE, Watson GC, Radda GK, Clarke K. Uncoupling proteins in human heart. Lancet 2004;364:1786-1788.
44. Murray AJ, Panagia M, Hauton D, Gibbons GF, Clarke K. Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels. Diabetes 2005;54:3496-3502.
45. Clapham JC, Arch Jr, Chapman H, Haynes A, Lister C, Moore GB et al. Mice over-expressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 2000;406:415-418.
46. Vidal-Puig AJ, Grujic D, Zhang CY, Hagen T, Boss O, Ido Y et al. Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem 2000;275:16258-16266.
47. Echtay KS, Esteves TC, PakayJL,Jekabsons MB, Lambert AJ, Portero-Otin M et al. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling. Embo J 2003;22:4103-4110.
48. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA et al. Super-oxide activates mitochondrial uncoupling proteins. Nature 2002;415:96-99.
49. Brand MD, PakayJL, Ocloo A, KokoszkaJ, Wallace DC, Brookes PS et al. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J 2005;392:353-362.
50. YAm Agishi SI, Edelstein D, Du XL, KanedaY, Guzman M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 2001;276:25096-25100.
51. Herlein JA, Fink BD, O'Malley Y, Sivitz WI. Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology 2009;150:46-55.
52. Boudina S, Bugger H, Sena S, O'Neill BT, Zaha VG, Ilkun O et al. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 2009;119:1272-1283.
53. Skulachev VP. Anion carriers in fatty acid-mediated physiological uncoupling. J Bioenerg Biomembr 1999;31:431-445.
54. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mech-anism of production of reactive oxygen species in mitochondria. FEBS Lett 1997;416: 15-18.
55. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide pro-duction from different sites in the mitochondrial electron transport chain. J Biol Chem 2002;277:44784-44790.
56. Skulachev VP. Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 1996; 29:169-202.
57. + exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. J Appl Physiol 2008;105:1706-1713.
58. Zhou L, Aon MA, Almas T, Cortassa S, Winslow RL, O'Rourke B. A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network. PLoS Comput Biol 6:e1000657
59. Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 1992;256:628-632.
60. Marra G, Cotroneo P, Pitocco D, Manto A, Di Leo MA, Ruotolo V et al. Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated type 1 diabetes: a case for gender difference. Diabetes Care 2002; 25:370-375.
61. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. The role of oxi-dative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Dia-betes Association and the German Diabetes Society. Diabetes Metab Res Rev 2001; 17:189-212.
62. Van Dam PS, Van Asbeck BS, Erkelens DW, MarxJJ, Gispen WH, Bravenboer B. The role of oxidative stress in neuropathy and other diabetic complications. Diabetes Metab Rev 1995;11:181-192.
63. Jay D, Hitomi H, Griendling KK Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med 2006;40:183-192.
64. Nishikawa T, Edelstein D, Du XL, YAm Agishi S, Matsumura T, Kaneda Y et al. Normalizing mitochondrial superoxide production blocks three pathways of hypergly-caemic dAm Age. Nature 2000;404:787-790.
65. +-ATPase and myosin heavy chain isozyme switch. Diabetologia 2006;49:1434-1446.
66. Turko IV, Li L, Aulak KS, Stuehr DJ, ChangJY, Murad F. Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mito-chondria in diabetes. J Biol Chem 2003;278:33972-33977.
67. Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC et al. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 2004; 53:1336-1343.
68. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection ofcardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes 2006;55: 798-805.
69. Santos DL, Palmeira CM, Seica R, DiasJ, MesquitaJ, Moreno AJ et al. Diabetes and mitochondrial oxidative stress: a study using heart mitochondria from the diabetic Goto-Kakizaki rat. Mol Cell Biochem 2003;246:163-170.
70. Conti M, Renaud IM, Poirier B, Michel O, Belair MF, Mandet C et al. High levels of myocardial antioxidant defense in aging nondiabetic normotensive Zucker obese rats. Am J Physiol Regul Integr Comp Physiol 2004;286:R793-R800.
71. Balaban RS. Cardiac energy metabolism homeostasis: role ofcytosolic calcium. J Mol Cell Cardiol 2002;34:1259-1271.
72. Isenberg G, Han S, Schiefer A, Wendt-Gallitelli MF. Changes in mitochondrial calcium concentration during the cardiac contraction cycle. Cardiovasc Res 1993; 27:1800-1809.
73. + concentration in heart mitochondria by entrapped fura-2 and quin2. Biochem J 1987;248:609-613.
74. Denton RM, Randle PJ, Martin BR. Stimulation by calcium ions of pyruvate dehydro-genase phosphate phosphatase. Biochem J 1972;128:161-163.
75. Nichols BJ, Denton RM. Towards the molecular basis for the regulation of mito-chondrial dehydrogenases by calcium ions. Mol Cell Biochem 1995;149-150: 203-212.
76. Duchen MR. Ca(2+)-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J 1992;283:41-50.
77. Hansford RG, Zorov D. Role of mitochondrial calcium transport in the control of substrate oxidation. Mol Cell Biochem 1998;184:359-369.
78. Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R. Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 1999;96:13807-13812.
79. Robb-Gaspers LD, Burnett P, Rutter GA, Denton RM, Rizzuto R, Thomas AP. Inte-grating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J 1998;17:4987-5000.
80. Territo PR, Mootha VK, French SA, Balaban RS. Ca(2+) activation of heart mito-chondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase. Am J Physiol Cell Physiol 2000;278:C423-C435.
81. Duchen MR. Roles of mitochondria in health and disease. Diabetes 2004;53(Suppl. 1):S96-S102.
82. Pierce GN, Dhalla NS. Heart mitochondrial function in chronic experimental dia-betes in rats. Can J Cardiol 1985;1:48-54.
83. Tanaka Y, Konno N, Kako KJ. Mitochondrial dysfunction observed in situ in cardio-myocytes of rats in experimental diabetes. Cardiovasc Res 1992;26:409-414.
84. + handling in ventricular myocytes isolated from diabetic rats. Am J Physiol 1996;270: H1529-H1537.
85. +]i responses to isoproterenol and cAMP in isolated cardiomyocytes from experimental diabetic rats. Am J Physiol 1994; 266:H2334-H2342.
86. Bouchard RA, Bose D. Influence of experimental diabetes on sarcoplasmic reticulum function in rat ventricular muscle. Am J Physiol 1991;260:H341-H354.
87. Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol 1983;244:E528-E535.
88. +-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart. Diabetes 2001;50:2133-2138.
89. Zhong Y, Ahmed S, Grupp IL, Matlib MA. Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts. Am J Physiol Heart Circ Physiol 2001; 281:H1137-H1147.
90. Belke DD, Dillmann WH. Altered cardiac calcium handling in diabetes. Curr Hyper-tens Rep 2004;6:424-429.
91. Dhalla NS, Liu X, Panagia V, Takeda N. Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res 1998;40:239-247.
92. + transport. Circulation research 1995;77:88-97.
93. Zima AV, Blatter LA. Redox regulation of cardiac calcium channels and transporters. Cardiovasc Res 2006;71:310-321.
94. Oliveira PJ, Seica R, Coxito PM, Rolo AP, Palmeira CM, Santos MS et al. Enhanced permeability transition explainsthe reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS Lett 2003;554:511-514.
95. Dong F, Zhang X, Yang X, Esberg LB, Yang H, Zhang Z et al. Impaired cardiac con-tractile function in ventricular myocytes from leptin-deficient ob/ob obese mice. J Endocrinol 2006;188:25-36.
96. + handling defects in cardiomyocytes of ob/ob mice. Diabetes 2005;54: 2375-2381. (Pubitemid 41134265)
97. Belke DD, Swanson EA, Dillmann WH. Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 2004;53:3201-3208.
98. Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev2004;18:357-368.
99. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V et al. Mechan-isms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999;98:115-124.
100. Lehman JJ, Barger PM, Kovacs A, SaffitzJE, Medeiros DM, Kelly DP. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 2000;106:847-856.
101. Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, SaffitzJE et al. Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res 2004;94:525-533.
102. Arany Z, He H, Lin J, Hoyer K, Handschin C, Toka O et al. Transcriptional coacti-vator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 2005;1:259-271
103. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributorto reduced cardiac efficiency in diabetes. Physiology (Bethesda) 2006;21:250-258.
104. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132: 27-42.
105. Nishida K, YAm Aguchi O, Otsu K Crosstalk between autophagy and apoptosis in heart disease. Circ Res 2008;103:343-351.
106. Turko IV, Murad F. Quantitative protein profiling in heart mitochondria from dia-betic rats. J Biol Chem 2003;278:35844-35849.
107. Hamblin M, Friedman DB, Hill S, Caprioli RM, Smith HM, Hill MF. Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy. J Mol Cell Cardiol 2007;42:884-895.
108. Hu Y, SuarezJ, Fricovsky E, Wang H, Scott BT, Trauger SA et al. Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J Biol Chem 2009;284:547-555.
109. Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 2002;109:629-639.
110. Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM et al. Mouse and human resistins impair glucose transport in primary mouse cardi-omyocytes, and oligomerization is required for this biological action. J Biol Chem 2005;280:31679-31685.
111. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med 2004;10: 1384-1389.
112. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K et al. Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK-and COX-2-dependent mechanisms. Nat Med 2005;11:1096-1103.
113. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, MiyagawaJ et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79-83.
114. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001;7:947-953.
115. YAm Auchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al. The fatderived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941-946.
116. Civitarese AE, Ukropcova B, Carling S, Hulver M, DeFronzo RA, Mandarino L et al. Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 2006;4: 75-87.
117. Iwabu M, YAm Auchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M et al. Adipo-nectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 2010;464:1313-1319.
118. Dabkowski ER, Williamson CL, Bukowski VC, Chapman RS, Leonard SS, Peer CJ et al. Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. Am J Physiol Heart Circ Physiol 2009;296:H359-H369.
119. Miki T, Miura T, Hotta H, Tanno M, Yano T, Sato T et al. Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeability transition. Diabetes 2009;58:2863-2872.
120. Yu T, Sheu SS, Robotham JL, Yoon Y. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 2008;79:341-351.
121. KajsturaJ, Fiordaliso F, Andreoli AM, Li B, Chimenti S, Medow MS et al. IGF-1 over-expression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 2001;50:1414-1424.
122. Nielsen LB, Bartels ED, Bollano E. Overexpression of apolipoprotein B in the heart impedes cardiactriglyceride accumulation and development ofcardiac dysfunction in diabetic mice. J Biol Chem 2002;277:27014-27020.
123. Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes 2008;57:3297-3306.
124. Wold LE, Ren J. Streptozotocin directly impairs cardiac contractile function in iso-lated ventricular myocytes via a p38 map kinase-dependent oxidative stress mechanism. Biochem Biophys Res Commun 2004;318:1066-1071.
125. SuarezJ, Scott B, Dillmann WH. Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol 2008;295:R1439-R1445.
126. +-ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats. J Physiol Biochem 2006;62:1-8.
127. Golfman LS, Wilson CR, Sharma S, Burgmaier M, Young ME, Guthrie PH et al. Acti-vation of PPARgamma enhances myocardial glucose oxidation and improves con-tractile function in isolated working hearts of ZDF rats. Am J Physiol Endocrinol Metab 2005;289:E328-E336.
128. Chandler MP, Morgan EE, McElfresh TA, Kung TA, RennisonJH, Hoit BD et al. Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats. Am J Physiol Heart Circ Physiol 2007;293:H1609-H1616.
129. Iltis I, Kober F, Desrois M, Dalmasso C, Lan C, Portha B et al. Defective myocardial blood flow and altered function of the left ventricle in type 2 diabetic rats: a non-invasive in vivo study using perfusion and cine magnetic resonance imaging. Invest Radiol 2005;40:19-26.
130. + exchanger contributes to left ventricu-lar hypertrophy in the Goto-Kakizaki rat model oftype 2 diabetes: critical role of Akt. Diabetologia 2007;50:1335-1344.
131. Finck BN, Han X, Courtois M, Aimond F, Nerbonne JM, Kovacs A et al. A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis ofdiabetic cardiomyopathy: modulation by dietary fat content Proc Natl Acad Sci USA 2003;100:1226-1231.