E. Dale Abel
Associate 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 relied heavily on transgenic and gene-targeted mice (conventional as well as conditional and cell-type restricted KO mice) to address many of these questions. 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. Boudina S, Abel ED (2007) Diabetic Cardiomyopathy Revisited. Circulation, In Press
2. Boudina S, Abel ED (2006) Mitochondrial uncoupling: A key contributor to reduced cardiac efficiency in diabetes. Physiology 21:250-258
3. 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
4. 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
5. 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
6. O’Neill BT, Abel ED (2005) Akt1 in the cardiovascular system: friend or foe? Journal of Clinical Investigation 115:2059-2064
7. 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)
8. 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. Endocrinology146:5341-5349
9. 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
10. 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-1a deficient mice exhibit multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLOS Biology 3(4)e101
11. 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
12. 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
13. 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
14. 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
15. Tian R, Abel ED (2001) The responses of GLUT4 deficient hearts to ischemia underscore the importance of glycolysis. Circulation 103:2961-2966
16. 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
Reviews and Editorials:
1. Abel ED (2005) Metabolic perturbations in the diabetic heart: Mechanisms and molecular targets. Drug Discovery Today: Disease Mechanisms 2:115-122
2. Abel ED (2005) Myocardial insulin resistance and cardiac complications of diabetes. Curr. Drug Targets -Immune, Endocrine and Metabolic Disorders 5:219-226
3. Abel ED (2004) Insulin signaling in cardiac muscle: Lessons from genetically engineered mouse models. Curr. Reports in Hypertension 6:416-423
4. Abel ED (2004) Glucose transport in the heart. Frontiers in Bioscience 9:201-215
5. Vidal-Puig AJ, Abel ED (2004) Insulin resistance and cardiovascular disease-New insights from genetics. In Handbook of Experimental Pharmacology -Volume: Cardiovascular Pharmacogenetics . Edited by Martin R. Wilkins. Heidelberg. Springer-Verlag 243-279
6. Abel ED (2002) Glucose transporters and cardiac function. Insights from heart selective GLUT4 knockout mice. In, Frontiers in animal diabetes research . Volume 3. " Insulin signaling: From cultured cells to animal models." Eds. G. Grunberger and Y. Zick 397-408
7. McCowen KC, Abel ED (2000) The contribution of defects in insulin signaling in skeletal muscle to insulin resistance and Type 2 diabetes: cellular and molecular aspects. In Advances in Structural Biology. Malhotria S. Editor. JAI Press. Volume 6:41-64
