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Oxidative Stress Triggers Cardiac Fibrosis in the Heart of Diabetic Rats

Department of Experimental Medicine and Oncology (M.A., R.M., I.V., P.B., O.D.), University of Turin, 10125 Turin, Italy; Department of Clinical Pathophysiology (M.G.C., G.B.), University of Turin, 10126 Turin, Italy; Department of Animal and Human Biology (G.A.), University of Turin, 10123 Turin, Italy; and Department of Clinical and Biological Sciences (S.G.), University of Turin, San Luigi Hospital, 10043 Orbassano, Italy

Address all correspondence and requests for reprints to: Professor Giuseppe Boccuzzi, Department of Clinical Pathophysiology, University of Turin, Via Genova 3, 10126 Turin, Italy. E-mail: giuseppe.boccuzzi{at}unito.it.

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 wk in the diet [0.02%, wt/wt)] to rats with streptozotocin-induced diabetes. Oxidative balance, advanced glycated end products (AGEs) and AGE receptors, transcription factors nuclear factor-B and activator protein-1, and profibrogenic growth factors (connective tissue growth factor and TGFβ1) were determined in the left ventricle of treated and untreated streptozotocin-diabetic rats. Structural and ultrastructural 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 profibrogenic 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 ultrastructural changes and impairment of muscle function induced by experimental diabetes were minimized by DHEA treatment.

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