E. Dale Abel
Professor of Biochemistry and of Medicine
M.B.B.S. University of the West Indies
D.Phil. University of Oxford
Dale Abel's Lab Page
Dale Abel's PubMed Literature Search
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. Wright JJ, Kim J, Buchanan J, Boudina S, Bakirtzi K, Ilkun O, Theobald HA, Cooksey RC, Kanror KV, Abel ED (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high fat feeding. Cardiovasc Res. Jan 15
2. Boudina S, Bugger H, Sena S, O’Neill BT, Zaha VG, Ilkun O, Wright JJ, Mazumder PK, Palfreyman E, Tidwell TJ, Theobald H, Khalimonchuk O, Wayment B, Sheng X, Rodnick KJ, Centini R, Chen D, Litwin SE, Weimer BE, Abel ED (2009) Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation Mar 10;119(9):1272-83 Epub Feb 23
3. Sena S, Hu P, Zhang D, Wang X, Wayment B, Olsen C, Avelar E, Abel ED, Litwin SE (2009) Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after myocardial infarction. J Mol Cell Cardiol. Feb 26
4. Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, Jones D, Cooksey RC, Birnbaum MJ, McClain DA, Zhang QJ, Gale D, Wilson LJ, Abel ED (2009) Contribution of Insulin and Akt1 Signaling to Endothelial Nitric Oxide Synthase in the Regulation of Endothelial Function and Blood Pressure. Circ Res. Apr 2. [Epub ahead of print]
5. Bakirtzi K, Belfort G, Lopez-Coviella I, Kuruppu D, Cao L, Abel ED, Brownell AL, Kandror KV (2009) Cerebellar neurons possess a vesicular compartment structurally and functionally similar to Glut4-storage vesicles from peripheral insulin-sensitive tissues. J Neurosci. Apr 22;29(16):5193-201
6. Lehman JJ, Boudina S, Banke NH, Sambandam N, Han X, Young DM, Leone TC, Gross RW, Lewandowski ED, Abel ED, Kelly DP (2008) The Transcriptional Coactivator PGC-1{alpha} is Essential for Maximal and Efficient Cardiac Mitochondrial Fatty Acid Oxidation and Lipid Homeostasis. Am J Physiol Heart Circ Physiol. 295(1):H185-96
7. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED, Goldberg IJ (2008) Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res. Oct;49(10):2101-12
8. Kim J, Wende AR, Sena S, Theobald HA, Soto J, Sloan C, Wayment BE, Litwin SE, Holzenberger M, LeRoith D, Abel ED (2008) Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. Mol Endocrinol. Nov;22(11):2531-43
9. Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA, Yun UJ, McQueen AP, Wayment B, Litwin SE, Abel ED (2008) Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes Nov;57(11):2924-32
10. Abel ED, Litwin SE, Sweeny GD (2008) Cardiac remodeling in obesity. Physiological Reviews 88(2):389-419
