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Excess Protein O‐GlcNAcylation and the Progression of Diabetic Cardiomyopathy
Author(s) -
Fricovsky Eduardo Santiago,
Suarez Jorge,
Ihm Sang-Hyun,
Scott Brian T.,
Suarez-Ramirez Jorge A.,
Villarreal Francisco J.,
Dillmann Wolfgang H.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.759.1
Subject(s) - medicine , endocrinology , hyperinsulinemia , diastole , diabetic cardiomyopathy , cardiac function curve , cardiomyopathy , diabetes mellitus , insulin resistance , heart failure , biology , chemistry , blood pressure
We examined the hypothesis that enzymatic protein O‐GlcNAcylation plays a role in the development of diabetic cardiomyopathy (DC) in a mouse model of type 2 diabetes (DM2). Mice injected with low‐dose STZ and fed high‐fat diet developed hyperglycemia and obesity. After 1 month of treatment, DM2 mice showed increased BW, impaired FBG and glucose tolerance, and hyperinsulinemia. Echo evaluation revealed LV diastolic dysfunction by 2 months which was associated with increased overall cardiac protein and nuclear transcription factor Sp1 O‐GlcNAcylation. By 4 months systolic dysfunction was observed and SERCA2a expression decreased by 50%. Levels of the rate limiting enzyme of the hexosamine pathway GFAT were increased as early as 1 month. Fatty acids, which are elevated in DM2, were linked to excessive protein O‐GlcNAcylation levels as cultured cardiac myocytes 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 is associated with increased cardiac protein O‐GlcNAcylation and increased O‐GlcNAcylation levels of key calcium handling proteins. Furthermore, 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 DC in DM2.