Disruption of calcium homeostasis in cardiomyocytes underlies cardiac structural and functional changes in severe sepsis

• Published in: PloS one Vol. 8; no. 7; p. e68809
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-07-2013; Public Library of Science (PLoS)
• Subjects: Actin; Actins - metabolism; Animals; Animals, Newborn; Biology; Blotting, Western; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium homeostasis; Calpain; Calpain - metabolism; Cardiomyocytes; Cardiomyopathy; Cecum - drug effects; Cecum - pathology; Cells, Cultured; Dantrolene - pharmacology; Delivery contracts; Departments; Dismantling; Dystrophin; Dystrophin - metabolism; Filaments; Fluorescent Antibody Technique; Glycoproteins; Health aspects; Heart; Heart cells; Heart diseases; Hemodynamics - drug effects; Homeostasis; Homeostasis - drug effects; Hospitals; Infection; Intensive care units; Intracellular Space - metabolism; Ligation; Medical prognosis; Medicine; Mice; Mice, Inbred C57BL; Morbidity; Mortality; Muscle contraction; Myocardium - metabolism; Myocardium - pathology; Myocardium - ultrastructure; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Myosin; Myosin Heavy Chains - metabolism; Neonates; Pathogenesis; Pathology; Permeability; Phagosomes; Prognosis; Proteasomes; Proteins; Punctures; Rodents; Sarcomeres - drug effects; Sarcomeres - metabolism; Sepsis; Sepsis - pathology; Sepsis - physiopathology; Stroke Volume - drug effects; Structure-function relationships; Studies; Survival; Survival Analysis; Utrophin; Vacuoles; Verapamil; Verapamil - pharmacology; Brazil; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068809

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 [Ca(2+)]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.