Diabetes-induced myocardial structural changes: Role of endothelin-1 and its receptors

Several metabolic abnormalities may be triggered secondary to hyperglycemia in diabetes. Some of these abnormalities may alter expression of vasoactiv e Factors in the target organs of diabetic complications. We investigated a lterations of endothelin-1 (ET-1) and its receptors, ETA and ETB, and assoc iated structural changes in the myocardium of streptozotocin-induced diabet ic rats after 6 months of hyperglycemia. We Further assessed the preventive effects of an ET-receptor antagonist bosentan(TM) on these changes. Compar ed to the non-diabetic. age- and sex-matched control animals, diabetic rats showed hyperglycemia, glucosuria, reduced body weight gain and elevated gl ycated Hb levels, Measurement of ET-1, ETA and ETB mRNAs by semiquantitativ e RT-PCR showed significantly increased mRNA levels in the hearts of diabet ic rats. Treatment with bosentan(TM) failed to reduce ET-1 or ETA mRNA expr ession in diabetes, however ETA mRNA expression was reduced. Immunocytochem ically, ET-1 was detected in the cardiomyocytes. endothelium and smooth mus cle cells of the larger blood vessels and was increased in diabetes, Autora diographic localization of ET-1 receptors, using I-125-ET-1, showed increas ed binding in the endothelium and myocardium of diabetic animals. Histologi cally, focal fibrous scarring with apoptotic cardiomyocytes, consistent wit h changes secondary to microvascular occlusion, was only present in the dia betic rats, In keeping with focal fibrosis, myocardium from diabetic rats f urther showed significantly increased mRNA expression of two extracellular matrix protein transcripts, fibronectin and collagen alpha 1(IV) which were completely prevented by treatment with bosentan(TM) These data suggest that hyperglycemia-induced upregulation of the ET-system in the heart may be important in the pathogenesis of cardiac involvement i n diabetes. (C) 2000 Academic Press.