Dystrophin and its associated proteins in the pathogenesis of doxorubicin-induced cardiomyopathy

• Grant number: 10/13199-1
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2010
• End date: September 30, 2012
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marcos Antonio Rossi
• Grantee: Marcos Antonio Rossi
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Benedito Carlos Maciel ; Cibele Maria Prado Zinni ; Lygia Maria Mouri Malvestio ; Mara Rúbia Nunes Celes ; Marcus Vinicius Simões ; Valdecir Blefari

Abstract

Anthracyclines are natural antibiotics, originally isolated from the bacterium Streptomyces peucetius, and widely used as anticancer drugs. Doxorubicin (adriamycin) and daunorubicin are part of the class of anthracyclines, which have a little structural difference, but that interferes with its spectrum of activity; doxorubicin has a wider spectrum, being one of the most effective antineoplasic agents against tumors in man. There are other currently available anthracyclines, such as idarubicin and epirubicin. Cancer treatment with anthracyclines, especially doxorubicin, can be toxic through the cumulative effect in the body. In particular, the main factor limiting the use of anthracyclines is a dose-dependent cardiotoxicity with the development of cardiomyopathy and heart failure. The morphological and ultrastructural alterations observed in the doxorubicin cardiomyopathy has been described as vacuolar degeneration, disorganization or loss of myofibrils, dilatation of sarcoplasmic reticulum, mitochondrial swelling and disruption of mitochondrial cristae, and interstitial fibrosis. The loss of myofibrils and vacuolar degeneration of cardiomyocytes are marked changes in this type of cardiomyopathy. These changes are progressive and cause death of cardiomyocytes. Besides the cardiotoxicity of doxorubicin on nucleic acids and on the integrity of cell membranes of cardiomyocytes, the cytoskeleton and the extracellular matrix components of cardiomyocytes can be affected in doxorubicin-induced cardiomyopathy. This structural integrity is maintained by the presence of proteins that form a link between the intracellular cytoskeleton and the extracellular matrix. The groups of structural proteins involved in this connection are: the dystrophin-glycoprotein complex, vinculin-integrin interaction, and spectrin-binding face of the membrane. The organization and interaction between these proteins are important for understanding the cellular mechanisms involved in the mechanical dysfunction in cardiomyopathies. This study proposes to test the hypothesis that doxorubicin-induced cardiomyopathy could be related to reduction of dystrophin and associated proteins expression in rat hearts as mechanism implicated in the development of cardiomyopathy and heart failure. This project proposes to: (a) to evaluate the expression, qualitatively and quantitatively, of proteins of the dystrophin glycoprotein complex (DGC) and of the extracellular matrix in myocardium of animals treated with doxorubicin using the immunofluorescence staining, real-time PCR and Western blot; (b) evaluate the in vivo cardiac function by echocardiography; (c) test the hypothesis of the possible role of calcium in the intrinsic mechanism of loss of dystrophin and associated glycoproteins in the development of cardiomyopathy induced by doxorubicin with calcium blocker drugs. This project could provide a highly significant benefit in this specific area of knowledge, providing a single intrinsic mechanism in the pathogenesis of dilated cardiomyopathy induced by anthracyclines, particularly doxorubicin. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PRADO, CIBELE M.; CELES, MARA R. N.; MALVESTIO, LYGIA M.; CAMPOS, ERICA C.; SILVA, JOAO S.; JELICKS, LINDA A.; TANOWITZ, HERBERT B.; ROSSI, MARCOS A.. Early dystrophin disruption in the pathogenesis of experimental chronic Chagas cardiomyopathy. Microbes and Infection, v. 14, n. 1, p. 59-68, JAN 2012. (10/13199-1, 09/17787-8, 10/19216-5, 10/18629-4, 09/54010-1)

CELES, MARA R. N.; MALVESTIO, LYGIA M.; SUADICANI, SYLVIA O.; PRADO, CIBELE M.; FIGUEIREDO, MARIA J.; CAMPOS, ERICA C.; FREITAS, ANA C. S.; SPRAY, DAVID C.; TANOWITZ, HERBERT B.; DA SILVA, JOAO S.; et al. Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis. PLoS One, v. 8, n. 7, JUL 23 2013. (10/13199-1, 09/17787-8, 10/19216-5, 10/18629-4, 09/54010-1, 09/02942-8)

CAMPOS, ERICA C.; O'CONNELL, JOAO L.; MALVESTIO, LYGIA M.; DIAS ROMANO, MINNA M.; RAMOS, SIMONE G.; CELES, MARA RUBIA N.; PRADO, CIBELE M.; SIMOES, MARCUS V.; ROSSI, MARCOS A.. Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy. European Journal of Pharmacology, v. 670, n. 2-3, p. 541-553, NOV 30 2011. (10/13199-1, 09/17787-8, 10/19216-5, 09/54010-1, 09/02942-8)

O'CONNELL, JOAO LUCAS; DIAS ROMANO, MINNA MOREIRA; CAMPOS PULICI, ERICA C.; CARVALHO, EDUARDO E. V.; DE SOUZA, FERNANDA R.; TANAKA, DENISE M.; MACIEL, BENEDITO CARLOS; SALGADO, HELIO C.; FAZAN-JUNIOR, RUBENS; ROSSI, MARCOS A.; et al. Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes. EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY, v. 69, n. 4, p. 213-219, APR 2017. (10/13199-1)