Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1

• Published in: Diabetologia Vol. 45; no. 8; pp. 1172 - 1181
• Main Authors: MARFELLA, R, D'AMICO, M, DI FILIPPO, C, PIEGARI, E, NAPPO, F, ESPOSITO, K, BERRINO, L, ROSSI, F, GIUGLIANO, D
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-08-2002; Springer Nature B.V
• Subjects: Angiogenesis; Animals; Associated diseases and complications; Biological and medical sciences; Blood Glucose - analysis; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - pathology; DNA-Binding Proteins - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Evolution; Geriatrics; Glucose; Heart attacks; Hemodynamics; Hyperglycemia; Hyperglycemia - etiology; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemia; Male; Medical sciences; Metabolic disorders; Mortality; Myocardial Infarction - etiology; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium - metabolism; Myocardium - pathology; Nuclear Proteins - metabolism; rac1 GTP-Binding Protein - metabolism; Rats; Rats, Sprague-Dawley; Reference Values; Transcription Factors; Endocrinopathy; Heart; Animal model; Oxygen; Rat; Diabetes mellitus; Rodentia; Cardiovascular disease; Coronary heart disease; Myocardial disease; Isolated organ; Vertebrata; Mammalia; Complication; Circulatory system
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-002-0882-x

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 1alpha (HIF-1alpha) in the rat.
We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1 alpha gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration.
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-1alpha 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-1alpha. 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-1alpha and Rac1, which were prevented by glutathione infusion (0.3 mmol/l) were also observed.
Both hyperglycaemia and high glucose concentrations increased basal HIF-1alpha 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-1alpha gene. These changes are reversed, totally or partially, by normoglycaemia or glutathione suggesting a role for reactive oxygen species generation brought about by hyperglycaemia.