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 #
5P01HL057278-14
Application #
8119130
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liang, Isabella Y
Project Start
1997-09-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
14
Fiscal Year
2011
Total Cost
$2,129,374
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Beirowski, Bogdan; Babetto, Elisabetta; Golden, Judith P et al. (2014) Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Nat Neurosci 17:1351-61
Lei, Xiaoyong; Bone, Robert N; Ali, Tomader et al. (2014) Evidence of contribution of iPLA2?-mediated events during islet ?-cell apoptosis due to proinflammatory cytokines suggests a role for iPLA2? in T1D development. Endocrinology 155:3352-64
Pacheco, Sophia A; Hsu, Fong-Fu; Powers, Katelyn M et al. (2013) MmpL11 protein transports mycolic acid-containing lipids to the mycobacterial cell wall and contributes to biofilm formation in Mycobacterium smegmatis. J Biol Chem 288:24213-22
Lei, Xiaoyong; Bone, Robert N; Ali, Tomader et al. (2013) Genetic modulation of islet ?-cell iPLA?? expression provides evidence for its impact on ?-cell apoptosis and autophagy. Islets 5:29-44
Kuda, Ondrej; Pietka, Terri A; Demianova, Zuzana et al. (2013) Sulfo-N-succinimidyl oleate (SSO) inhibits fatty acid uptake and signaling for intracellular calcium via binding CD36 lysine 164: SSO also inhibits oxidized low density lipoprotein uptake by macrophages. J Biol Chem 288:15547-55
Yang, Kui; Dilthey, Beverly Gibson; Gross, Richard W (2013) Identification and quantitation of fatty acid double bond positional isomers: a shotgun lipidomics approach using charge-switch derivatization. Anal Chem 85:9742-50
Viader, Andreu; Sasaki, Yo; Kim, Sungsu et al. (2013) Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77:886-98
Kiebish, Michael A; Yang, Kui; Liu, Xinping et al. (2013) Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome. J Lipid Res 54:1312-25
Jenkins, Christopher M; Yang, Jingyue; Gross, Richard W (2013) Mechanism-based inhibition of iPLA2? demonstrates a highly reactive cysteine residue (C651) that interacts with the active site: mass spectrometric elucidation of the mechanisms underlying inhibition. Biochemistry 52:4250-63
Kiebish, Michael A; Yang, Kui; Sims, Harold F et al. (2012) Myocardial regulation of lipidomic flux by cardiolipin synthase: setting the beat for bioenergetic efficiency. J Biol Chem 287:25086-97

Showing the most recent 10 out of 180 publications