| Full text | |
| Author(s): |
Campos, Erica C.
[1]
;
O'Connell, Joao L.
[2]
;
Malvestio, Lygia M.
[1]
;
Dias Romano, Minna M.
[2]
;
Ramos, Simone G.
[1]
;
Celes, Mara Rubia N.
[1]
;
Prado, Cibele M.
[1]
;
Simoes, Marcus V.
[3]
;
Rossi, Marcos A.
[4, 1]
Total Authors: 9
|
| Affiliation: | [1] Univ Sao Paulo, Lab Cellular & Mol Cardiol, Dept Pathol, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Univ Hosp, Div Cardiol, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Internal Med Cardiol, BR-14049900 Ribeirao Preto, SP - Brazil
[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | European Journal of Pharmacology; v. 670, n. 2-3, p. 541-553, NOV 30 2011. |
| Web of Science Citations: | 20 |
| Abstract | |
The critical importance of dystrophin to cardiomyocyte contraction and sarcolemmal and myofibers integrity, led us to test the hypothesis that dystrophin reduction/loss could be involved in the pathogenesis of doxorubicin-induced cardiomyopathy, in order to determine a possible specific structural culprit behind heart failure. Rats received total cumulative doses of doxorubicin during 2 weeks: 3.75, 7.5, and 15 mg/kg. Controls rats received saline. Fourteen days after the last injection, hearts were collected for light and electron microscopy, immunofluorescence and western blot. The cardiac function was evaluated 7 and 14 days after drug or saline. Additionally, dantrolene (5 mg/kg), a calcium-blocking agent that binds to cardiac ryanodine receptors, was administered to controls and doxorubicin-treated rats (15 mg/kg). This study offers novel and mechanistic data to clarify molecular events that occur in the myocardium in doxorubicin-induced chronic cardiomyopathy. Doxorubicin led to a marked reduction/loss in dystrophin membrane localization in cardiomyocytes and left ventricular dysfunction, which might constitute, in association with sarcomeric actin/myosin proteins disruption, the structural basis of doxorubicin-induced cardiac depression. Moreover, increased sarcolemmal permeability suggests functional impairment of the dystrophin-glycoprotein complex in cardiac myofibers and/or oxidative damage. Increased expression of calpain, a calcium-dependent protease, was markedly increased in cardiomyocytes of doxorubicin-treated rats. Dantrolene improved survival rate and preserved myocardial dystrophin, calpain levels and cardiac function, which supports the opinion that calpain mediates dystrophin loss and myofibrils degradation in doxorubicin-treated rats. Studies are needed to further elucidate this mechanism, mainly regarding specific calpain inhibitors, which may provide new interventional pathways to prevent doxorubicin-induced cardiomyopathy. (C) 2011 Elsevier B.V. All rights reserved. (AU) | |
| FAPESP's process: | 10/13199-1 - Dystrophin and its associated proteins in the pathogenesis of doxorubicin-induced cardiomyopathy |
| Grantee: | Marcos Antonio Rossi |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 09/17787-8 - High blood pressure, cardiac hypertrophy, heart failure and dystrophin-glycoprotein complex |
| Grantee: | Cibele Maria Prado Zinni |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| FAPESP's process: | 10/19216-5 - Hypertension, cardiac hypertrophy and cardiac failure and dystrophin glycoproteins |
| Grantee: | Cibele Maria Prado Zinni |
| Support Opportunities: | Scholarships in Brazil - Young Researchers |
| FAPESP's process: | 09/54010-1 - Sepsis and septic shock: functional and morphological changes in the heart. An experimental study in mice |
| Grantee: | Helio Cesar Salgado |
| Support Opportunities: | Multi-user Equipment Program |
| FAPESP's process: | 09/02942-8 - "In vitro" evaluation of the expression of dystrophin in cardiomyocytes submitted to different stimuli. |
| Grantee: | Lygia Maria Mouri Malvestio |
| Support Opportunities: | Scholarships in Brazil - Master |