ALTERED ACTIVITIES OF TRANSCRIPTION FACTORS AND THEIR RELATED GENE-EXPRESSION IN CARDIAC TISSUES OF DIABETIC RATS

Gene regulation in the cardiovascular tissues of diabetic subjects has been reported to be altered. To examine abnormal activities in transc ription factors as a possible cause of this altered gene regulation, w e studied the activity of two redox-sensitive transcription factors-nu clear factor-KB (NF-kappa B) and activating protein-1 (AP-l)-and the c hange in the mRNA content of heme oxygenase-l, which is regulated by t hese transcription factors in the cardiac tissues of rats with strepto zotocin-induced diabetes. Increased activity of NF-KB and AP-1 but not nuclear transcription-activating factor, as determined by an electrop horetic mobility shift assay, was found in the hearts of 4-week diabet ic rats. Glycemic control by a subcutaneous injection of insulin preve nted these diabetes-induced changes in transcription factor activity. In accordance with these changes, the mRNA content of heme oxygenase-l was increased fourfold in 4-week diabetic rats and threefold in 24-we ek diabetic rats as compared with control rats CP < 0.01 and P < 0.05, respectively). Insulin treatment also consistently prevented changes in the mRNA content of heme oxygenase-l. The oral administration of an antioxidant, probucol, to these diabetic rats partially prevented the elevation of the activity of both NF kappa B and AP-1, and normalized the mRNA content of heme oxygenase-l without producing any change in the plasma glucose concentration. These results suggest that elevated oxidative stress is involved in the activation of the transcription fa ctors NF-KB and AP1 in the cardiac tissues of diabetic rats, and that these abnormal activities of transcription factors could be associated with the altered gene regulation observed in the cardiovascular tissu es of diabetic rats.