Diabetic cardiomyopathy is a complex disorder that results from maladaptive changes in cardiac lipid metabolism in the diabetic state. The prolonged and nearly exclusive reliance on fatty acid substrate to fuel contractile function in myocardium ultimately leads to an overt metabolic myopathy that is characterized clinically by the presence of diastolic dysfunction, ventricular hypertrophy and bioenergetic inefficiency that collectively increase the morbidity and mortality in diabetic patients. Diabetic patients are subject not only to the aggressive vascular atherosclerosis characteristic of the diabetic state, but are also predisposed to the increased adverse effects of myocardial ischemia on metabolically compromised myocardium. The unifying hypothesis of the program project is that the excessive utilization of fatty acid substrate to fuel hemodynamic function at the expense of glucose in diabetic myocardium results in a metabolic imbalance that leads to the in appropriate activation of phospholipases precipitating membrane dysfunction. These alterations in membrane function compromise the bioenergetic efficiency and metabolic flexibility of diabetic myocardium and result in the increased susceptibility of diabetic myocardium to ischemic damage. The chronic excessive use of fatty acids results in the accumulation of toxic lipid metabolites such as acyl-CoA that serve dual roles in both cardiac bioenergetics and in cardiac myocyte signaling. Accumulation of acyl-CoA leads to the activation of intracellular calcium independent phospholipases (iPLA2s) (Project 1) that compromise membrane function and lead to alterations in mitochondrial bioenergetic efficiency through changes in cardiolipin content and molecular species composition (Project 2). Moreover, the chronic and excessive utilization of CD36 to facilitate fatty acid transport and trafficking ultimately leads to dysfunctional changes in CD36 signaling functions (Project 3). This distortion is propagated by chronic decreased insulin signaling in diabetic myocardium leading to decreased Akt signaling (Project 4) that has multiple effects on myocardium including the decreased phosphorylation of FOXO1 preventing physiologic insulin-mediated suppression of CD36 transcription and translation. The prolonged activation of phospholipases and CD36 in the diabetic state alters membrane function, fatty acid transport and trafficking that propagates the metabolic myopathy and altered cellular signaling in diabetic myocardium. Ultimately, mitochondrial dysfunction leads to a decrease in the ability to oxidize lipids efficiently promoting a feed forward cycle of cardiac dysfunction. The proposed research extends original discoveries made by Program investigators that are fundamental to the biochemical and pathologic sequelae of the diabetic state. The program provides a highly synergistic and interactive foundation through the integrated scientific themes of the component projects that are efficiently interfaced with the enabling technologies of lipidomics, proteomics. metabolomics and multiparametric physiologic assessments of myocardial function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL057278-15
Application #
8274294
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wang, Lan-Hsiang
Project Start
1997-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2012
Total Cost
$2,077,068
Indirect Cost
$710,576
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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