Inhibition of Calcium Influx during Hypoxia/Reoxygenation in Primary Cultured Rat Hepatocytes

Crénesse, Dominique; Hugues, Michel; Ferre, C.; Poirée, Jean‐Claude; Benoliel, J.J.; Dolisi, C.; Gugenheim, Jean

doi:10.1159/000028278

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…Several laboratories have used an isolated hepatocyte model, designed to mimic ischemia and reperfusion, to measure changes in [Ca 2+ ] cyt in hepatocytes subject to hypoxia. A sustained increase in [Ca 2+ ] cyt in isolated hepatocytes is observed on reoxygenation following hypoxia or anoxia (68)(69)(70).…”

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

“…Some evidence has been obtained to indicate that the IR-induced increases in total Ca 2+ in the intact liver and increases in [Ca 2+ ] cyt in hepatocytes are due to enhanced Ca 2+ inflow across the plasma membrane (68,69). Although the Ca 2+ -permeable channels responsible for this Ca 2+ inflow have not yet been identified, studies with an hepatocyte cell line (liver epithelial clone 9) have shown that ROS activate a 16 pS nonselective cation channel which could admit Ca 2+ (47).…”

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

“…While these agents, at relatively high concentrations, do seem to give some protection, this is unlikely to be due to effects on Ca 2+ channels in hepatocytes (which do not express voltage-operated Ca 2+ channels [58]), but may be due to effects of the antagonists on Kupffer cells and/or on other nonhepatocyte cell types or on other proteins in hepatocytes (64,68,75,76; but see also Ref. 77).…”

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

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Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

et al. 2006

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Liver resection and liver transplantation have been successful in the treatment of liver tumors and end-stage liver disease. This success has led to an expansion in the pool of patients potentially treatable by liver surgery and, in the case of transplantation, to a shortage of liver donors. At present, there are significant numbers of potential candidates for liver resection and liver donation who have fatty livers, are aged, or have livers damaged by chemotherapy. All of these are at high risk for ischemic reperfusion (IR) injury. The aims of this review are to assess current knowledge of the clinical effectiveness of ischemic preconditioning and intermittent ischemia in reducing IR damage in liver surgery; to evaluate the use of bile flow as a sensitive indicator of IR liver damage; and to analyze the molecular mechanisms, especially intracellular Ca2+, involved in IR injury and ischemic preconditioning. It is concluded that bile flow is a sensitive indicator of IR injury. Together with reactive oxygen species (ROS) and other extracellular and intracellular signaling molecules, intracellular Ca2+ in hepatocytes plays a key role in the normal regulation of bile flow and in IR-induced injury and cell death. Ischemic preconditioning is an effective strategy to reduce IR injury but there is considerable scope for improvement, especially in patients with fatty and aged livers. The development of effective new strategies to reduce IR injury will depend on improved understanding of the molecular mechanisms involved, especially by gaining a better perspective of the relative importance of the various intrahepatocyte signaling pathways involved.

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Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

Section: Intracellular Ca 2+ As a Mediator Of Hepatocyte Injury Inducmentioning

confidence: 99%

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Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

et al. 2006

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“…Furthermore, Crenesse/Tornieri/Laurens/Heurteaux/ Cursio/Gugenheim/Schmid-Alliana Striggow et al [4] have shown that L-type channel blockers inhibit ROCCs in rat hepatocytes. In previous studies, we have shown that hypoxia-reoxygenation phases increased calcium influx [5] and that diltiazem effectively protected hepatocytes from calcium invasion [6]. Hepatocyte calcium entry during ischemia-reperfusion may not exclusively occur through a putative receptor-activated Ca 2+ channel, but also through an increased passive membrane Ca 2+ leak [7].…”

Section: Introductionmentioning

confidence: 99%

Diltiazem Reduces Apoptosis in Rat Hepatocytes Subjected to Warm Hypoxia-Reoxygenation

Crénesse

Tornieri²,

Laurens³

et al. 2002

Pharmacology

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Interruption of hepatic blood flow is necessary in surgery, but the liver is sensitive to ischemia and reperfusion. Hypoxia induces an increase in intracellular calcium concentration. In previous studies, we have shown that hypoxia-reoxygenation (H/R) increased calcium influx and induced JNK₁/SAPK₁ activation which was involved in the triggering of apoptosis. The aim of this study was to demonstrate that diltiazem, a calcium inhibitor, reduced JNK₁/SAPK₁ activation and consequently could decrease H/R-induced apoptosis. Experiments were performed, in the presence of diltiazem, on primary cultured rat hepatocytes, subjected to warm H/R phases and in a liver ischemia-reperfusion model. The activation status of JNK₁/SAPK₁ was evaluated by immunoprecipitation and immunohistolocalisation experiments, while apoptosis was assessed by measuring caspase activity and by TUNEL labeling. Diltiazem inhibited H/R-induced JNK₁/SAPK₁ activation and decreased apoptosis. It could be used to improve postoperative liver function.

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“…This lack of oxygen and nutrients sets off a cascade of biochemical reactions that ultimately results in the necrosis and apoptosis of cells [2]. 228 J Invest Surg Downloaded from informahealthcare.com by The University of Manchester on 12/20/14 For personal use only.When liver cells undergo I/R injury, an increase in cytoplasmic calcium levels is observed soon after the reintroduction of oxygen [21][22][23]. This is partly due to the release of internal calcium stores (discussed in 229 J Invest Surg Downloaded from informahealthcare.com by The University of Manchester on 12/20/14…”

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confidence: 99%

Intracellular Calcium Signaling Pathways during Liver Ischemia and Reperfusion

Chang

Chehab

Kink

et al. 2010

Journal of Investigative Surgery

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Calcium plays a major role in intracellular signaling mechanisms during ischemia reperfusion (I/R) injury of a liver cell. Under ischemic conditions, the absence of oxygen arrests oxidative phosphorylation, thereby eliminating the energy source by which hepatocellular mechanisms maintain homeostasis of calcium. This, in turn, leaves nonselective plasma membrane influx pores unopposed and results in a net increase in intracellular calcium concentrations. Subsequent reperfusion marks the onset and progression of apoptosis and necrosis, as it involves inflammatory responses as well as free-radical formation due to re-oxygenation of cells. These processes destroy the structural integrity of organelles, leading to disruptive redistribution of calcium between cellular and subcellular compartments. This initial elevation and later imbalance of intracellular calcium concentrations associated with I/R induce various molecular responses within each organelle. In the cytoplasm, a series of pro-apoptotic pathways involving various calcium sensitive enzymes are activated. The injury is further exacerbated in the endoplasmic reticulum (ER) due to the malfunction of mechanisms responsible for intracellular calcium sequestration. Both the mitochondria and the nucleus are also adversely affected, as their structural integrity and physiologic functions are disrupted. To date, however, the precise pathophysiology of these calcium-mediated signaling pathways is not fully understood due to its complex nature. This review aims to systematically examine the current literature about individual molecular signaling pathways in the cytoplasm, ER, mitochondria, and the nucleus prior to causing time-sensitive progression of permanent tissue injury.

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Inhibition of Calcium Influx during Hypoxia/Reoxygenation in Primary Cultured Rat Hepatocytes

Cited by 13 publications

References 27 publications

Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

Hepatic Ischemia-Reperfusion Injury: Roles of Ca2+ and Other Intracellular Mediators of Impaired Bile Flow and Hepatocyte Damage

Diltiazem Reduces Apoptosis in Rat Hepatocytes Subjected to Warm Hypoxia-Reoxygenation

Intracellular Calcium Signaling Pathways during Liver Ischemia and Reperfusion

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