Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1
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Aims/hypothesis. This study aimed to evaluate the effects of hyperglycaemia on the evolution of myocardial infarction and the expression of the transcriptional factor for angiogenesis hypoxia-inducible factor 1α (HIF-1α) in the rat.
Methods. We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1α gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration.
Results. In streptozotocin (STZ)-diabetic rats (in vivo study), myocardial infarct size was greater (p<0.01) in hyperglycaemic rats (22 mmol/l) than in normoglycaemic (7 mmol/l) or non-diabetic rats. In euglycaemic conditions, basal expression of HIF-1α mRNA was not appreciable, but increased steadily after ischaemia (762±86%, p<0.001); this response was blunted in hyperglycaemic STZ-rats (6.8±6% of the control, p<0.001) and improved in euglycaemic STZ-rats (58±10%). The changes in myocardial Rac1 mRNA expression paralleled those of HIF-1α. In isolated hearts from non-diabetic rats (in vitro study), perfusion with high glucose (33 mmol/l) produced an infarct size (58±2% of the area at risk) not different from that obtained in hyperglycaemic STZ-rats (57±2%). Similar changes in the expression of HIF-1α and Rac1, which were prevented by glutathione infusion (0.3 mmol/l) were also observed.
Conclusion/interpretation. Both hyperglycaemia and high glucose concentrations increased basal HIF-1α and Rac1 expression, suggesting a state of pseudohypoxia. These findings show that myocardial infarct size in the rat is increased in hyperglycaemic conditions and is associated with a reduced expression of the HIF-1α gene. These changes are reversed, totally or partially, by normoglycaemia or glutathione suggesting a role for reactive oxygen species generation brought about by hyperglycaemia.