title: Oxidative stress triggers cardiac fibrosis in the heart of diabetic rats.
abstract: 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-kappaB and activator protein-1, and profibrogenic growth factors (connective tissue growth factor and TGFbeta1) 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.
authors: Department of Experimental Medicine and Oncology, University of Turin, Via Genova 3, 10126 Turin, Italy.
authors: Manuela
authors: M
authors: Aragno
authors: Raffaella
authors: R
authors: Mastrocola
authors: Giuseppe
authors: G
authors: Alloatti
authors: Ilenia
authors: I
authors: Vercellinatto
authors: Paola
authors: P
authors: Bardini
authors: Stefano
authors: S
authors: Geuna
authors: Maria Graziella
authors: MG
authors: Catalano
authors: Oliviero
authors: O
authors: Danni
authors: Giuseppe
authors: G
authors: Boccuzzi
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor; D003687:Dehydroepiandrosterone / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006331:Heart Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D013311:Streptozocin; D018808:Transcription Factor AP-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D017127:Glycation End Products, Advanced; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000067759:Receptor for Advanced Glycation End Products; D018342:Receptors, Adrenergic, beta-1; D011971:Receptors, Immunologic; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D003687:Dehydroepiandrosterone; D013311:Streptozocin