Journal
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
Volume 303, Issue 7, Pages R689-R699Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00548.2011
Keywords
Type 2 diabetes mellitus; high-fat diet; diabetic cardiomyopathy; protein glycosylation
Categories
Funding
- National Heart, Lung, and Blood Institute Grant [HL-66917]
- Supplement to Promote Diversity in Health-Related Research [3R01HL-066917-10S1]
- National Institutes of Health/National Institue on Minority Health and Health Disparities [P60 MD000220]
- University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences
- P. Robert Majumder Charitable Foundation
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Fricovsky ES, Suarez J, Ihm S, Scott BT, Suarez-Ramirez JA, Banerjee I, Torres-Gonzalez M, Wang H, Ellrott I, Maya-Ramos L, Villarreal F, Dillmann WH. Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol 303: R689-R699, 2012. First published August 8, 2012; doi:10.1152/ajpregu.00548.2011.-We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardio-graphic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca2+ ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine: fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.
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