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

Mara R N Celes, Lygia M. Malvestio, Sylvia O. Suadicani, Cibele M. Prado, Maria J. Figueiredo, Erica C. Campos, Ana C S Freitas, David C. Spray, Herbert B. Tanowitz, João S. da Silva, Marcos A. Rossi

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere68809
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 23 2013

Fingerprint

calpain
Calpain
Cardiac Myocytes
Dystrophin
Actins
homeostasis
Sepsis
dystrophin
Homeostasis
actin
Calcium
calcium
Myosins
cardiomyopathy
myosin
Dantrolene
Cardiomyopathies
Intensive care units
survival rate
Myosin Heavy Chains

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Celes, M. R. N., Malvestio, L. M., Suadicani, S. O., Prado, C. M., Figueiredo, M. J., Campos, E. C., ... Rossi, M. A. (2013). Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis. PLoS One, 8(7), [e68809]. https://doi.org/10.1371/journal.pone.0068809

Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis. / 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, João S.; Rossi, Marcos A.

In: PLoS One, Vol. 8, No. 7, e68809, 23.07.2013.

Research output: Contribution to journalArticle

Celes, MRN, Malvestio, LM, Suadicani, SO, Prado, CM, Figueiredo, MJ, Campos, EC, Freitas, ACS, Spray, DC, Tanowitz, HB, da Silva, JS & Rossi, MA 2013, 'Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis', PLoS One, vol. 8, no. 7, e68809. https://doi.org/10.1371/journal.pone.0068809
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, João S. ; Rossi, Marcos A. / Disruption of Calcium Homeostasis in Cardiomyocytes Underlies Cardiac Structural and Functional Changes in Severe Sepsis. In: PLoS One. 2013 ; Vol. 8, No. 7.
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