Clinical and experimental investigations have indicated that diabetes per se can lead to a deterioration of cardiac function that cannot be solely attributable to coronary artery disease. What is apparent from most models of heart failure is that ventricular myocytes undergo similar phenotypic and genotypic changes (defined as a cardiomyopathy) in response to various metabolic and systemic stresses. This investigation is designed to test the hypothesis that cellular responses to type I and type 2 diabetes converge early on in the diseases, and manifest in abnormal cardiomyocyte intracellular Ca2+ regulation. The applicants will test this hypothesis by determining intracellular signaling pathways that contribute to the development of abnormal excitation- contraction (E-C) coupling in two distinct models of early stages of diabetes: 1) culturing myocytes in a hyperglycemic milieu and 2) sucrose-feeding animals triggering the development of insulin resistance. Myocyte E-C coupling will be evaluated using biophysical measures (video-edge detection, electrophysiology and spectrofluorometry), and kinase activity and expression of specific proteins using biochemical and immunoblot assays. Pharmacological interventions (both in cell culture and in vivo) will be used to evaluate the roles of target kinases (i.e., PKC, PKA and CaMKII) in the pathogenesis of impaired E-C coupling. The working hypothesis is that changes in regulatory protein activity precede overt changes in gene expression of ion channels and membrane pumps, such that these changes are the initial cause of myocyte dysfunction rather than a compensatory phenotypic change induced to preserve contractile function. This investigation will focus on cellular mechanisms which contribute to abnormal E-C coupling in diabetes and are common to those in other models of heart failure (e.g., depressed K+ conductance and SR Ca2+ fluxes). The development of cellular insulin resistance is likely to be a key factor in the etiology of diabetic cardiomyopathy and may represent the recapitulation of fetal gene expression, as shown for hypertrophic myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL066895-01
Application #
6310324
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (S2))
Program Officer
Linder, Barbara
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$347,350
Indirect Cost
Name
University of New England
Department
Physiology
Type
Schools of Osteopathy
DUNS #
071735252
City
Biddeford
State
ME
Country
United States
Zip Code
04005
Lebeche, Djamel; Davidoff, Amy J; Hajjar, Roger J (2008) Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. Nat Clin Pract Cardiovasc Med 5:715-24
Matsui, Takashi; Davidoff, Amy J (2007) Assessment of PI-3 kinase and Akt in ischemic heart diseases in diabetes. Methods Mol Med 139:329-38
Fulop, Norbert; Mason, Meredith M; Dutta, Kaushik et al. (2007) Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol 292:C1370-8
Davidoff, Amy J (2006) Convergence of glucose- and fatty acid-induced abnormal myocardial excitation-contraction coupling and insulin signalling. Clin Exp Pharmacol Physiol 33:152-8
Schwanke, M L; Dutta, K; Podolin, D A et al. (2006) Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage. Diabetologia 49:1097-105
Dutta, Kaushik; Carmody, Marybeth W; Cala, Steven E et al. (2002) Depressed PKA activity contributes to impaired SERCA function and is linked to the pathogenesis of glucose-induced cardiomyopathy. J Mol Cell Cardiol 34:985-96