The hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance

Simple item page
dc.contributor.authorRajamani U.
dc.contributor.authorJoseph D.
dc.contributor.authorRoux S.
dc.contributor.authorEssop M.F.
dc.date.accessioned2011-05-25T08:49:57Z
dc.date.available2011-05-25T08:49:57Z
dc.date.issued2011
dc.description.abstractAims: Type 2 diabetes is characterized by deranged metabolic pathways that may result in cardiovascular complications. For example, hyperglycaemia promotes flux through the hexosamine biosynthetic pathway (HBP) leading to greater O-GlcNAcylation of target proteins, with pathophysiological outcomes. This study investigated mechanisms whereby increased HBP flux elicits myocardial apoptosis in a rat model of diet-induced hyperglycaemia/insulin resistance. Methods: Four-week-old male Wistar rats were fed a high-fat diet (86days) after which insulin resistance was assessed vs. matched controls. Oxidative stress was evaluated, and apoptotic peptide levels, BAD phosphorylation and overall O-GlcNAcylation assessed by immunoblotting. Protein-specific O-GlcNAcylation and BAD-Bcl-2 dimerization were determined by immunoprecipitation and Western blotting. Results: Rats consuming the high-fat diet exhibited a moderate elevation in body weight, higher fasting insulin and glucose levels, and insulin resistance vs. controls. Overall protein O-GlcNAcylation was increased in hyperglycaemic/insulin-resistant hearts. In parallel, myocardial peptide levels of apoptotic markers (caspase-3, cytochrome-c, BAD) were significantly higher with insulin resistance. To gain mechanistic insight into our findings, we evaluated O-GlcNAcylation of BAD, a pro-apoptotic Bcl-2 homolog. Here we found increased BAD O-GlcNAcylation and decreased BAD phosphorylation (Ser136) in hyperglycaemic/insulin-resistant rat hearts. These data are in agreement with competition by phosphorylation and O-GlcNAcylation for the same or neighbouring site(s) on target proteins. Moreover, we observed increased BAD-Bcl-2 dimerization in hyperglycaemic/insulin-resistant hearts. Conclusion: The main finding of this study is that increased apoptosis in hyperglycaemic/insulin-resistant hearts can also be mediated through HBP-induced BAD O-GlcNAcylation and greater formation of BAD-Bcl-2 dimers (pro-apoptotic). © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.
dc.description.versionArticle
dc.identifier.citationActa Physiologica
dc.identifier.citation202
dc.identifier.citation2
dc.identifier.citation151
dc.identifier.citation157
dc.identifier.issn17481708
dc.identifier.other10.1111/j.1748-1716.2011.02275.x
dc.identifier.urihttp://hdl.handle.net/10019.1/14759
dc.titleThe hexosamine biosynthetic pathway can mediate myocardial apoptosis in a rat model of diet-induced insulin resistance
dc.typeArticle
Files
Collections
Stellenbosch University - Scopus Publications