E2f1 deletion attenuates infarct-induced ventricular remodeling without affecting O-GlcNAcylation
Autor: | Mitali G. Chitre, Bethany W. Long, Linda T. Harrison, Lauren A. Higgins, Giuseppe Militello, Shizuka Uchida, Daniel W. Riggs, Anna M. Gumpert, Kenneth R. Brittian, Steven P. Jones, Timothy N. Audam, Andrea Jurkovic, Senthilkumar K. Muthusamy, Sujith Dassanayaka |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine endocrine system Glycosylation Physiology Angiogenesis Myocardial Infarction 030204 cardiovascular system & hematology N-Acetylglucosaminyltransferases Ventricular Function Left Article 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Physiology (medical) medicine Animals E2F1 Myocardial infarction Ventricular remodeling Transcription factor Mice Knockout Ventricular Remodeling business.industry Myocardium Wild type medicine.disease Coronary Vessels beta-N-Acetylhexosaminidases Capillaries Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology Heart failure Female biological phenomena cell phenomena and immunity Cardiology and Cardiovascular Medicine business E2F1 Transcription Factor Gene Deletion |
Zdroj: | Basic Res Cardiol |
ISSN: | 1435-1803 0300-8428 |
DOI: | 10.1007/s00395-019-0737-y |
Popis: | Several post-translational modifications figure prominently in ventricular remodeling. The beta-O-linkage of N-acetylglucosamine (O-GlcNAc) to proteins has emerged as an important signal in the cardiovascular system. Although there are limited insights about the regulation of the biosynthetic pathway that gives rise to the O-GlcNAc post-translational modification, much remains to be elucidated regarding the enzymes, such as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which regulate the presence/absence of O-GlcNAcylation. Recently, we showed that the transcription factor, E2F1, could negatively regulate OGT and OGA expression in vitro. The present study sought to determine whether E2f1 deletion would improve post-infarct ventricular function by de-repressing expression of OGT and OGA. Male and female mice were subjected to non-reperfused myocardial infarction (MI) and followed for 1 or 4 week. MI significantly increased E2F1 expression. Deletion of E2f1 alone was not sufficient to alter OGT or OGA expression in a naïve setting. Cardiac dysfunction was significantly attenuated at 1-week post-MI in E2f1-ablated mice. During chronic heart failure, E2f1 deletion also attenuated cardiac dysfunction. Despite the improvement in function, OGT and OGA expression was not normalized and protein O-GlcNAcyltion was not changed at 1-week post-MI. OGA expression was significantly upregulated at 4-week post-MI but overall protein O-GlcNAcylation was not changed. As an alternative explanation, we also performed guided transcriptional profiling of predicted targets of E2F1, which indicated potential differences in cardiac metabolism, angiogenesis, and apoptosis. E2f1 ablation increased heart size and preserved remote zone capillary density at 1-week post-MI. During chronic heart failure, cardiomyocytes in the remote zone of E2f1-deleted hearts were larger than wildtype. These data indicate that, overall, E2f1 exerts a deleterious effect on ventricular remodeling. Thus, E2f1 deletion improves ventricular remodeling with limited impact on enzymes regulating O-GlcNAcylation. |
Databáze: | OpenAIRE |
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