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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis

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Celes, Mara R. N. [1, 2, 3] ; Malvestio, Lygia M. [2] ; Suadicani, Sylvia O. [4] ; Prado, Cibele M. [2] ; Figueiredo, Maria J. [2] ; Campos, Erica C. [2] ; Freitas, Ana C. S. [2] ; Spray, David C. [5] ; Tanowitz, Herbert B. [3] ; da Silva, Joao S. [6, 7] ; Rossi, Marcos A. [2]
Total Authors: 11
[1] Univ Fed Goias, Inst Trop Pathol & Publ Hlth, Goiania, Go - Brazil
[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pathol, Sao Paulo - Brazil
[3] Yeshiva Univ, Albert Einstein Coll Med, Dept Pathol, Bronx, NY - USA
[4] Yeshiva Univ, Albert Einstein Coll Med, Dept Urol, Bronx, NY - USA
[5] Yeshiva Univ, Albert Einstein Coll Med, Dept Med Cardiol, Bronx, NY - USA
[6] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Immunol, Sao Paulo - Brazil
[7] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biochem, Sao Paulo - Brazil
Total Affiliations: 7
Document type: Journal article
Source: PLoS One; v. 8, n. 7 JUL 23 2013.
Web of Science Citations: 18

Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of {[}Ca2+](i) and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors. (AU)

FAPESP's process: 10/19216-5 - Hypertension, cardiac hypertrophy and cardiac failure and dystrophin glycoproteins
Grantee:Cibele Maria Prado Zinni
Support type: Scholarships in Brazil - Young Researchers
FAPESP's process: 09/17787-8 - High blood pressure, cardiac hypertrophy, heart failure and dystrophin-glycoprotein complex
Grantee:Cibele Maria Prado Zinni
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 10/18629-4 - The role of calcium, calpain, pro-inflammatory cytokines and hypoxia on dystrophin expression in cardiomyocytes subjected to different stimuli: an in vitro study
Grantee:Lygia Maria Mouri Malvestio
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 10/13199-1 - Dystrophin and its associated proteins in the pathogenesis of doxorubicin-induced cardiomyopathy
Grantee:Marcos Antonio Rossi
Support type: Regular Research Grants
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 type: 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 type: Scholarships in Brazil - Master