Resveratrol treatment reduces cardiac progenitor cell dysfunction and prevents morpho-functional ventricular remodeling in type-1 diabetic rats

• Published in: PloS one Vol. 7; no. 6; p. e39836
• Main Authors: Delucchi, Francesca, Berni, Roberta, Frati, Caterina, Cavalli, Stefano, Graiani, Gallia, Sala, Roberto, Chaponnier, Christine, Gabbiani, Giulio, Calani, Luca, Del Rio, Daniele, Bocchi, Leonardo, Lagrasta, Costanza, Quaini, Federico, Stilli, Donatella
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.06.2012; Public Library of Science (PLoS)
• Subjects: Actins - metabolism; Animals; Antioxidants; Apoptosis; Apoptosis - drug effects; Autophagy; Biology; Blood Glucose - metabolism; Body Weight - drug effects; Bone marrow; Calcium; Calcium (intracellular); Calcium Signaling - drug effects; Calcium signalling; Cardiomyocytes; Cardiomyopathy; Cell Count; Coculture Techniques; Compartments; Cytokines; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - physiopathology; Endothelial Cells - drug effects; Endothelial Cells - pathology; Environmental impact; Enzymes; Gene expression; Heart; Heart diseases; Heart failure; Hemodynamics; Hemodynamics - drug effects; HMGB1 Protein - metabolism; Hyperglycemia; Immunoblotting; Immunohistochemistry; Immunology; Inflammation; Intracellular; Intracellular Space - drug effects; Intracellular Space - metabolism; Laboratory animals; Male; Medicine; Morphometry; Muscle contraction; Myocardium - enzymology; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neutrophils; Oxidative stress; Physiological aspects; Progenitor cells; Prolongation; Proteins; Rats; Rats, Wistar; Remodeling; Resveratrol; Rodents; Stem Cells - drug effects; Stem Cells - pathology; Stilbenes - pharmacology; Stilbenes - therapeutic use; Streptozocin; Type 1 diabetes; Ventricle; Ventricular Remodeling - drug effects; Wound healing; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039836

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n = 64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic "milieu" on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.