Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: Detrimental role of Na+–Ca2+ exchanger

Magi, Simona; Nasti, Annamaria Assunta; Gratteri, Santo; Castaldo, Pasqualina; Bompadre, Stefano; Amoroso, Salvatore; Lariccia, Vincenzo

doi:10.1016/j.ejphar.2014.10.054

Cited by 30 publications

(27 citation statements)

References 61 publications

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“…Previous studies have reported that LPS perturbs intracellular Ca 2+ homeostasis in microglial cells, cardiomyocytes, and lung microvessels (Choi et al 2002;Beck et al 2008;Wang et al 2009;Kandasamy et al 2013;Magi et al 2015). In contrast, the present study showed that human sperm [Ca 2+ ] i was unaffected by LPS (Fig.…”

Section: +contrasting

confidence: 55%

“…5C, D). This discrepancy may be attributed to two factors: first, LPS changes [Ca 2+ ] i by regulating the expression of genes encoding Ca 2+ and Na + /Ca 2+ channels in microglial cells, cardiomyocytes, and lung microvessels (Choi et al 2002;Beck et al 2008;Wang et al 2009;Kandasamy et al 2013;Magi et al 2015). However, sperm lack active transcriptional machinery so that LPS could not affect intracellular Ca 2+ homeostasis by regulating gene expression.…”

Section: +mentioning

confidence: 97%

“…Many studies have shown that LPS regulates cell functions by modulating the expression of related genes (Kajihara et al 2006;Beck et al 2008;Bhushan et al 2008;Okazaki et al 2009;Brecchia et al 2010;Zhang et al 2014;Magi et al 2015). However, unlike other cells, mature sperm are fully differentiated cells with highly condensed nuclei that lack active transcriptional machinery (Alasmari et al 2013).…”

Section: Discussionmentioning

confidence: 99%

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Lipopolysaccharide Compromises Human Sperm Function by Reducing Intracellular cAMP

Zhang

et al. 2016

Tohoku J. Exp. Med.

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A worldwide decline in the quality of human semen is currently occurring. In mammals, sperm are produced from diploid stem-cell spermatogonia by spermatogenesis in testes and become mature in epididymis. Nevertheless, these biological processes can be affected by Gram-negative bacterial infection mediated by lipopolysaccharide (LPS), the major endotoxin of Gram-negative bacteria. It is well known that LPS can disturb spermatogenesis and affect sperm maturation and quality in vivo. However, the effect of LPS on the ejaculated mature sperm in vitro remains unclear. Thus, this study aimed to assess the in vitro toxicity of LPS on human sperm function and to elucidate the underlying mechanism. Human sperm were incubated with LPS (0.1-100 μg/ml) for 1-12 h in vitro and, subsequently, sperm viability, motility and capacitation, and the acrosome reaction were examined. LPS dose-dependently inhibited total and progressive motility and the ability to move through a viscous medium of the sperm but did not affect sperm viability, capacitation, and the acrosome reaction. To explore the underlying mechanism of LPS's actions, we examined the effects of LPS on the intracellular concentrations of cyclic adenosine monophosphate (cAMP) and calcium ([Ca 2+ ] i ) and protein-tyrosine phosphorylation of human sperm, which are key regulators of human sperm function. LPS decreased intracellular cAMP dose-dependently but had no effect on [Ca 2+ ] i and protein-tyrosine phosphorylation of human sperm. These findings suggest that LPS inhibits human sperm motility by decreasing intracellular cAMP.

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Section: +contrasting

confidence: 55%

Section: +mentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Lipopolysaccharide Compromises Human Sperm Function by Reducing Intracellular cAMP

Zhang

et al. 2016

Tohoku J. Exp. Med.

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“…We initially established an in vitro model of H/R based on two H9c2 clones 19 , H9c2-WT (not expressing endogenous NCX1 under our culture conditions 17,20 and H9c2-NCX1 (generated from H9c2-WT and stably expressing canine NCX1 17 ). When cells were subjected to 3 h of hypoxia followed by 5 h of reoxygenation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Maiolino

Castaldo

Lariccia

et al. 2017

Sci Rep

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Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial energy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here we investigated the role of NCX1 in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury.

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“…Wu & Liu [36] also found a 50 % reduced pump kinetics for PMCA 4 h following endotoxin treatment in a canine sepsis model. For involvement of NCX in LPS-induced sepsis, only one recent study reports increased NCX1 expression in septic rat hearts [20]. However, a functional analysis of Ca 2?…”

Section: Altered Cellular Ca 21 Homeostasis In Lps-induced Septic Carmentioning

confidence: 98%

Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca2+ removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan

et al. 2015

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Cardiac dysfunction is a common complication in sepsis and is characterized by forward pump failure. Hallmarks of septic cardiomyopathy are decreased myofibrillar contractility and reduced Ca(2+) sensitivity but it is still not clear whether reduced pump efficiency is predominantly a diastolic impairment. Moreover, a comprehensive picture of upstream Ca(2+) handling mechanisms and downstream myosin biomechanical parameters is still missing. Ca(2+)-sensitizing agents in sepsis may be promising but mechanistic insights for drugs like levosimendan are scarce. Here, we used an endotoxemic LPS rat model to study mechanisms of sepsis on in vivo hemodynamics, multicellular myofibrillar Ca(2+) sensitivity, in vitro cellular Ca(2+) homeostasis and subcellular actomyosin interaction with intracardiac catheters, force transducers, confocal Fluo-4 Ca(2+) recordings in paced cardiomyocytes, and in vitro motility assay, respectively. Left ventricular ejection fraction and myofibrillar Ca(2+) sensitivity were depressed in LPS animals but restored by levosimendan. Diastolic Ca(2+) transient kinetics was slowed down by LPS but ameliorated by levosimendan. Selectively blocking intracellular and sarcolemmal Ca(2+) extrusion pathways revealed minor contribution of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) to Ca(2+) transient diastole in LPS-evoked sepsis but rather depressed Na(+)/Ca(2+) exchanger and plasmalemmal Ca(2+) ATPase. This was mostly compensated by levosimendan. Actin sliding velocities were depressed in myosin heart extracts from LPS rats. We conclude that endotoxemia specifically impairs sarcolemmal diastolic Ca(2+) extrusion pathways resulting in intracellular diastolic Ca(2+) overload. Levosimendan, apart from stabilizing Ca(2+)-troponin C complexes, potently improves cellular Ca(2+) extrusion in the septic heart.

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Gram-negative endotoxin lipopolysaccharide induces cardiac hypertrophy: Detrimental role of Na+–Ca2+ exchanger

Cited by 30 publications

References 61 publications

Lipopolysaccharide Compromises Human Sperm Function by Reducing Intracellular cAMP

Lipopolysaccharide Compromises Human Sperm Function by Reducing Intracellular cAMP

Essential role of the Na+-Ca2+ exchanger (NCX) in glutamate-enhanced cell survival in cardiac cells exposed to hypoxia/reoxygenation

Septic cardiomyopathy in rat LPS-induced endotoxemia: relative contribution of cellular diastolic Ca2+ removal pathways, myofibrillar biomechanics properties and action of the cardiotonic drug levosimendan

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