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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: PLoS One; v. 8, n. 7 JUL 23 2013.
• Web of Science Citations: 18

Abstract

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: 10/13199-1 - 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: 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 Opportunities: Scholarships in Brazil - Doctorate (Direct)
• 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