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

Abstract

AIMS:

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 (86 days) 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).

• Authors: U Rajamani, D Joseph, S Roux, M F Essop
• Journal: Acta physiologica (Oxford, England) (Acta Physiol (Oxf)) Vol. 202 Issue 2 Pg. 151-7 (Jun 2011) ISSN: 1748-1716 [Electronic] England
• PMID: 21385329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

Chemical References

• Biomarkers
• Dietary Fats
• Hexosamines
• Proto-Oncogene Proteins c-bcl-2
• bcl-Associated Death Protein

Topics

• Animals
• Apoptosis (physiology)
• Biomarkers (metabolism)
• Biosynthetic Pathways (physiology)
• Diabetes Mellitus, Type 2 (metabolism)
• Diet (adverse effects)
• Dietary Fats
• Hexosamines (biosynthesis)
• Humans
• Hyperglycemia (metabolism)
• Insulin Resistance (physiology)
• Male
• Myocardium (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats
• Rats, Wistar
• bcl-Associated Death Protein (metabolism)