E. Dale Abel
Professor of Biochemistry and of Medicine
M.B.B.S. University of the West Indies
D.Phil. University of Oxford
Research
Our laboratory is focused on: (1) elucidating the molecular mechanisms that are responsible for cardiac failure in diabetes. (2) Elucidating the molecular signals that coordinate the mitochondrial and metabolic adaptations to cardiac growth. (3) Elucidating the mechanisms by which insulin and growth factor signaling regulate cardiac mitochondrial metabolism and the adaptation of the heart to stress. (4) Elucidating the role of mitochondrial dysfunction in the pathogenesis of insulin resistance, diabetes and its complications.
Our recent studies have underscored the importance of mitochondrial oxidative stress as a major mechanism leading to cardiac dysfunction in obesity and diabetes. We have shown for example that multiple abnormalities such as increased myocardial fatty acid delivery or impaired insulin signal transduction independently impair mitochondrial function and the expression of gene regulatory pathways that encode many mitochondrial proteins. We have used transgenic and gene targeting approaches (conventional as well as conditional and cell-type restricted KO mice) to perturb multiple components of the insulin signaling pathway in the heart or to perturb selective metabolic pathways involved in glucose or fatty acid metabolism that have identified mechanisms involved in cardiac dysfunction in obesity and diabetes. We have developed a comprehensive array of approaches such as measurement of mitochondrial energetics in subcellular organelles, determination of substrate flux in intact hearts, as well as cardiovascular phenotyping in intact mice. We are also using proteomics and gene arrays to identify novel insulin-regulated targets in the mitochondria and validating these results using cell-culture models and transcriptional assays.
References
1. Tabbi-Anneni I, Buchanan J, Cooksey RC, Abel ED (2008) Captopril normalizes insulin signaling and insulin-regulated substrate metabolism in obese (ob/ob) mouse hearts. Endocrinology, In Press
2. Abel ED, Litwin SE, Sweeney GD (2008) Cardiac remodeling in obesity. Physiological Reviews 88:389-419
3. Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213-3223
4. Hsueh WA, Abel ED, Breslow JL, Maeda N, Davis RC, Fisher EA, Dansky H, McClain DA, McIndoe R, Wassef MK, Rabadan-Diehl C, Goldberg IJ (2007) Recipes for creating animal models of diabetic cardiovascular disease. Circulation Research 100:1415-1427
5. O'Neill BT, Kim J, Wende AR, Theobald HA, Tuinei J, Buchanan J, Guo A, Zaha VG, Davis DK, Schell JC, Boudina S, Wayment B, Litwin SE, Shioi T, Izumo S, Birnbaum MJ, Abel ED (2007) A conserved role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial adaptations that accompany physiological cardiac hypertrophy. Cell Metabolism 6(4):294-306
6. Hao HX, Cardon CM, Swiatek W, Cooksey RC, Smith TL, Wilde J, Boudina S, Abel ED, McClain DA, Rutter J (2007) PAS kinase is required for normal cellular energy balance. Proc Natl Acad Sci USA 104(39):15466-71
7. Sena S, Rasmussen IR, Wende AR, McQueen AP, Theobald HA, Wilde N, Pereira RO, Litwin SE, Berger JP, Abel ED (2007) Cardiac Hypertrophy Caused by Peroxisome Proliferator Activated Receptor-Gamma Agonist Treatment Occurs Independently of Changes in Myocardial Insulin Signaling. Endocrinology 148:6047-53
8. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, Aziz S, Johnson JI, Bugger H, Zaha VG, Abel ED (2007) Mitochondrial energetics in the heart in obesity related diabetes: Direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56(10):2457-66
9. Boudina S, Abel ED (2006) Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology 21;250-258
10. Lelliot CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM, Bjursell M, Parker N, Curtis K, Campbell M, Hu P, Zhang D, Litwin SE, Zaha VG, Fountain KT, Boudina S, Jimenez-Linan M, Bloun M, Lopez M, Meirhaeghe A, Bohlooly M, Storlien L, Strömstedt M, Snaith M, Ore M, Abel ED, Cannon B, Vidal-Puig A (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function and cardiac performance. PLoS Biology 4(11):e369
11. Augustus AS, Buchanan J, Park TS, Hirata K, Noh HL, Sun J, Homma S, D'armiento J, Abel ED, Goldberg IJ (2006) Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. J Biol Chem. 281:8716-8723
12. Bugger H, Abel ED (2008) Molecular mechanisms of myocardial mitochondrial dysfunction in the metabolic syndrome. Clinical Science 114(3):195-210
13. Bray MS, Shaw CA, Moore MW, Garcia RA, Zanquetta MM, Durgan DJ, Jeong WJ, Tsai JY, Bugger H, Zhang D, Rohrwasser A, Rennison JH, Dyck JR, Litwin SE, Hardin PE, Chow CW, Chandler MP, Abel ED, Young ME (2008) Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism and gene expression. Am J Physiol Heart Circ Physiol 294(2):H1036-47
14. Durgan DJ, Smith JK, Hotze MA, Egbejimi O, Cuthbert KD, Zaha VG, Dyck JR, Abel ED, Young ME (2006) Distinct Transcriptional Regulation of Long-Chain Acyl-CoA Synthetase Isoforms and Cytosolic Thioesterase 1 in the Rodent Heart by Fatty Acids and Insulin. Am J Physiol Heart Circ Physiol 290:H2480-2497
15. O’Neill BT, Abel ED (2005) Akt1 in the cardiovascular system: friend or foe? Journal of Clinical Investigation 115;2059-2064
16. Abel ED (2005) Myocardial insulin resistance and cardiac complications of diabetes. Curr. Drug Targets –Immune, Endocrine and Metabolic Disorders 5;219-226
17. Boudina S, Sena S, O’Neill BT, Tathireddy P, Young ME, Abel ED (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impairs myocardial energetics in obesity. Circulation 112:2686-2695
18. McQueen AP, Zhang D, Hu P, Swenson L, Yang Y, Zaha VG, Hoffman JL, Yun UJ, Chakrabarti G, Wang Z, Albertine KH, Abel ED*, Litwin SE* (2005) Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density. J. Molecular and Cellular Cardiology 39:882-892 (* corresponding authors)
19. Buchanan J, Mazumder PK, Hu P, Chakrabarti G, Roberts MW, Yun UJ, Cooksey RC, Litwin SE, Abel ED (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146:5341-5349
20. Graveleau C, Zaha VG, Mohajer A, Banerjee RR, Dudley-Rucker N, Steppan CM, Rajala MW, Scherer PE, Ahima RS, Scherer PS, Lazar MA, Abel ED (2005) Mouse and human resistin impair glucose transport in primary mouse cardiomyocytes and oligomerization is required for this biological action. J. Biol. Chem. 280:31679-31685
21. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) PGC-1α deficient mice exhibit multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLOS Biology 3(4)e101
22. Rui T, Feng Q, Lei M, Peng T, Zhang J, Xu M, Abel ED, Xenocostas A, Kvietys PR (2005) Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion in vitro and in vivo: role of AP-1. Cardiovascular Research 65:719-727
23. Abel ED (2004) Insulin signaling in cardiac muscle: Lessons from genetically engineered mouse models. Curr. Reports in Hypertension 6:416-423
24. Abel ED (2004) Glucose transport in the heart. Frontiers in Bioscience 9:201-215
25. Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, Boudina S, Abel ED (2004) Impaired Cardiac Efficiency and Increased Fatty Acid Oxidation in Insulin Resistant ob/ob mouse hearts. Diabetes 53:2366-2374
26. Abel ED, Graveleau C, Betuing S, Pham M, Reay PA, Kandror V, Kupriyanova T, Xu Z, Kandror KV (2004) Regulation of IRAP expression and targeting in the insulin responsive vesicle compartment of GLUT4 deficient cardiomyocytes. Molecular Endocrinology 18:2491-2501
27. Shiojima I, Yefremashvili M, Luo Z, Kureishi Y, Takahashi A, Tao J, Rosenzweig A, Kahn CR, Abel ED, Walsh K (2002) Akt mediates postnatal cardiac growth in response to insulin and nutritional status. Journal of Biological Chemistry 277:37670-37677
28. Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, Zhang D, Cooksey RC, McClain DA, Litwin SE, Taegtmeyer H, Severson D, Kahn CR, Abel ED (2002) Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. Journal of Clinical Investigation 109:629-639
29. Tian R, Abel ED (2001) The responses of GLUT4 deficient hearts to ischemia underscore the importance of glycolysis. Circulation 103:2961-2966
30. Abel ED, Peroni O, Kim JK, Kim Y-B, Boss O, Hadro E, Minneman T, Shulman GI, Kahn BB (2001) Adipose selective targeting of the GLUT4 Gene impairs insulin action in muscle and liver. Nature 409:729-733
31. Abel ED, Kaulbach HC, Tian R, Hopkins Duffy J, Doetschman T, Minnemann T, Boers M-E, Hadro E, Oberste-Berghaus C, Quist W, Lowell BB, Ingwall JS, Kahn BB (1999) Cardiac hypertrophy with preserved contractile function following deletion of GLUT4 selectively in the heart. Journal of Clinical Investigation 104:1703-171
