Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis
Harvard University, Cambridge, Massachusetts, United States Critical Care Medicine
(Impact Factor: 6.31).
04/2005; 33(3):598-604. DOI: 10.1097/01.CCM.0000152223.27176.A6
Changes in cardiac function due to sepsis have been widely reported. However, the underlying mechanisms remain poorly understood. In the mammalian heart, myocyte function and intracellular calcium homeostasis are closely coupled. In this study we tested the hypothesis that alterations in cardiac calcium homeostasis due to sepsis underlie the observed myocyte dysfunction.
Randomized prospective animal study.
Male Sprague-Dawley rats weighing 250-275 g.
We induced sepsis by cecal ligation and puncture in the rat, which mimics the type of infection caused by perforation of the intestine in humans.
Forty-eight hours after cecal ligation and puncture, isolated cardiac ventricular cardiomyocytes demonstrated a 57% decreased peak systolic [Ca]. The time constant of the Ca transient increased 71% and 57% in myocytes obtained 24 hrs and 48 hrs after cecal ligation and puncture, respectively. The average shortening of cardiomyocytes 48 hrs after cecal ligation and puncture was significantly decreased. To investigate the cellular mechanisms of altered Ca transients and myocyte shortening, we measured Ca sparks, the spontaneous local Ca release events in cardiomyocytes at resting states. The Ca spark frequency progressively increased in myocytes 24 hrs and 48 hrs after cecal ligation and puncture. The total activity of sparks also increased compared with sham-operated animals. The overall leakage of sarcoplasmic reticulum Ca in resting states was increased in sepsis and resulted in reduced sarcoplasmic reticulum Ca content.
Abnormal Ca leakage from the sarcoplasmic reticulum contributes significantly to the depressed myocyte shortening in sepsis. In the future, modalities that prevent this Ca leakage may prove beneficial in the treatment of sepsis-induced myocyte shortening.
Available from: Ion A Hobai
- "Sex Age, wk Model Time Finding Hobai et al., 2013 (37) Mouse (C57Bl/6) M 12Y15 LPS (O111:B4), 25 mg/kg, i.p. 14 h Decreased Ca SR Ichinose et al., 2007 (40) Mouse (C57BL/6J) M 8Y16 LPS (O111:B4), 50 mg/kg, i.p. 7 h Decreased Ca SR Zhu et al., 2005 (38) Rat (Sprague-Dawley) M ? CLP 24 h ''Unchanged'' Ca SR Zhu et al., 2005 (38) Rat ( "
[Show abstract] [Hide abstract]
ABSTRACT: Sepsis induced cardiomyopathy (SIC) develops as the result of myocardial calcium (Ca) dysregulation. Here we reviewed all published studies that quantified the dysfunction of intracellular Ca transporters and the myofilaments in animal models of SIC.Cardiomyocytes isolated from septic animals showed, invariably, a decreased twitch amplitude, which is frequently caused by a decrease in the amplitude of cellular Ca transients (ΔCai) and sarcoplasmic reticulum (SR) Ca load (CaSR). Underlying these deficits, the L-type Ca channel is downregulated, through mechanisms that may involve adrenomedullin-mediated redox signaling. SR Ca pump (SERCA) is also inhibited, through oxidative modifications (sulphonylation) of one reactive thiol group (on Cys), and/or modulation of phospholamban. Diastolic Ca leak of ryanodine receptors is frequently increased. In contrast, Na/Ca exchange inhibition may play a partially compensatory role by increasing CaSR and ΔCai. The action potential is usually shortened. Myofilaments show a bidirectional regulation, with decreased Ca sensitivity in milder forms of disease (due to troponin I hyperphosphorylation) and a (redox mediated) increase in more severe forms. Most deficits occurred similarly in two different disease models, induced by either intraperitoneal administration of bacterial lipopolysaccharide (LPS) or cecal ligation and puncture (CLP).In conclusion, substantial cumulative evidence implicates various Ca transporters and the myofilaments in SIC pathology. What is less clear, however, is the identity and interplay of the signaling pathways that are responsible for Ca transporters dysfunction. With few exceptions, all studies we found used solely male animals. Identifying sex differences in Ca dysregulation in SIC becomes, therefore, another priority.
Shock (Augusta, Ga.) 08/2014; 43(1). DOI:10.1097/SHK.0000000000000261 · 3.05 Impact Factor
Available from: Simon M. Harrison
- "In summary, this study illustrates that simultaneous exposure of ventricular myocytes to TNF– α and IL-1β reduces cell contractility, the magnitude of the Ca 2+ transient and SR Ca 2+ content, effectively mimicking effects seen in CLP-induced sepsis . Enhanced spark frequency, propensity for spontaneous wave generation and subsequent triggered activity provides a proarrhythmic state which may contribute to the increased incidence of arrhythmia observed clinically in patients with sepsis. "
[Show abstract] [Hide abstract]
ABSTRACT: Sepsis is associated with ventricular dysfunction and increased incidence of atrial and ventricular arrhythmia however the underlying pro-arrhythmic mechanisms are unknown. Serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) are elevated during sepsis and affect Ca2+ regulation. We investigated whether pro-inflammatory cytokines disrupt cellular Ca2+ cycling leading to reduced contractility, but also increase the probability of pro-arrhythmic spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). Isolated rat ventricular myocytes were exposed to TNF-alpha (0.05 ng ml(-1)) and IL-1beta (2 ng ml(-1)) for 3 hr and then loaded with fura-2 or fluo-3 to record the intracellular Ca2+ concentration ([Ca2+](i)). Cytokine treatment decreased the amplitude of the spatially averaged Ca2+ transient and the associated contraction, induced asynchronous Ca2+ release during electrical stimulation, increased the frequency of localized Ca2+ release events, decreased the SR Ca2+ content and increased the frequency of spontaneous Ca2+ waves at any given cytoplasmic Ca2+. These data suggest that TNF-alpha and IL-1beta increase the SR Ca2+ leak from the SR, which contributes to the depressed Ca2+ transient and contractility. Increased susceptibility to spontaneous SR Ca2+ release may contribute to arrhythmias in sepsis as the resulting Ca2+ extrusion via NCX is electrogenic, leading to cell depolarisation.
Cell calcium 03/2010; 47(4):378-86. DOI:10.1016/j.ceca.2010.02.002 · 3.51 Impact Factor
Available from: Ravin Narain
- "Human septic sera induced gene expression Int J Clin Exp Med (2009) 2, 131-148 144 Increased concentrations of free intracellular Ca 2+ ions observed during sepsis   partially contribute to these metabolic disorders. Sepsis-induced LPL repression contributes to sepsis-associated lipid metabolic disorders in TNF-α-induced Ca 2+ dependent manner . "
[Show abstract] [Hide abstract]
ABSTRACT: To gain a better understanding of the gene expression changes that occurs during sepsis, we have performed a cDNA microarray study utilizing a tissue culture model that mimics human sepsis. This study utilized an in vitro model of cultured human fetal cardiac myocytes treated with 10% sera from septic patients or 10% sera from healthy volunteers. A 1700 cDNA expression microarray was used to compare the transcription profile from human cardiac myocytes treated with septic sera vs normal sera. Septic sera treatment of myocytes resulted in the down-regulation of 178 genes and the up-regulation of 4 genes. Our data indicate that septic sera induced cell cycle, metabolic, transcription factor and apoptotic gene expression changes in human myocytes. Identification and characterization of gene expression changes that occur during sepsis may lead to the development of novel therapeutics and diagnostics.
International Journal of Clinical and Experimental Medicine 02/2009; 2(2):131-48. · 1.28 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.