Diabetic cardiomyopathy is characterized by myocyte loss and myocardial fibrosis, leading to decreased elasticity and impaired contractile function. The study examines the downstream signaling whereby oxidative stress, induced by hyperglycemia, leads to myocardial fibrosis and impaired contractile function in the left ventricle of diabetic rats. It also examines the effects of dehydroepiandrosterone (DHEA), which prevents the oxidative damage induced by hyperglycemia in experimental models.

DHEA was administered for 6 weeks in the diet (0.02%, w/w) to rats with STZ-induced diabetes. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, transcription factors NFk-B and AP-1, and profibrogenic growth factors (CTGF and TGF-1) were determined in the left ventricle of treated and untreated STZ-diabetic rats. Structural and ultra-structural changes, and the contractile force developed by electrically-driven papillary muscles, under basal conditions and after stimulation with isoproterenol, were also evaluated.

Oxidative stress induced by hyperglycemia increased AGEs and AGE-receptors and triggered a cascade of signaling, eventually leading to interstitial fibrosis. DHEA treatment, by improving oxidative balance, counteracted the enhanced AGE-receptor activation and increase of pro-fibrogenic factors, and restored tissue levels of collagen I, collagen IV and fibronectin to those of control animals. Moreover, DHEA completely restored the contractility of isolated papillary muscle.

Oxidative stress led to cardiac fibrosis, the most important pathogenetic factor of the heart's impaired functional integrity in diabetes. Structural and ultra-structural changes and impairment of muscle function induced by experimental diabetes were minimized by DHEA treatment.