Molecular basis for calcium signaling in hepatic stellate cells

Kruglov, Emma A.; Correa, Paulo Renato A.V.; Arora, Gaurav; Jin, Yu; Nathanson, Michael H.; Dranoff, Jonathan A.

doi:10.1152/ajpgi.00401.2006

Cited by 30 publications

(25 citation statements)

References 34 publications

(49 reference statements)

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“…Early reports have shown secretion of prostaglandins F2 and D2 after stimulation with ATP (109). Recent studies revealed that P2Y receptors link extracellular ATP to inositol triphosphate-mediated cytosolic calcium signals resulting in localized calcium signaling and cell contraction (110,111).…”

Section: Purinergic Receptorsmentioning

confidence: 99%

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/ CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2-expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

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Section: Purinergic Receptorsmentioning

confidence: 99%

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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“…Resting HSCs usually locate in the perisinusoidal space with vitamin A-containing lipid droplets. However, their morphology and physiology alter dramatically during myofibroblastic transdifferentiation, also known as activation, which serves as the critical step in the initiation as well as progression of liver fibrosis [2,3]. The most important phenotypic alterations of activated HSCs, as defined by theirs actions in liver fibrogenesis, lie in the active proliferation, autocrine and/or paracrine fibrogenetic factors, inordinate ECM synthesis and secretion, and resistance to apoptosis, etc.…”

Section: Introductionmentioning

confidence: 99%

miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis

Guo

Pan

et al. 2009

Journal of Hepatology

253

218

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“…Following liver injury of any etiology, HSCs undergo a response known as ''activation,'' which is the transition of quiescent cells into proliferative, fibrogenic, and contractile myofibroblasts [2]. Several studies recently reported that the number of HSCs are increased associated with its biological properties of HSCs proliferation and counteration of apoptosis, when stimulated by fibrogenic stimuli [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Effects of upregulated expression of microRNA-16 on biological properties of culture-activated hepatic stellate cells

et al. 2009

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In our previous studies, we identified miR-16 as being downregulated during activation of hepatic stellate cells (HSCs) by microarray hybridization. However, the roles and related mechanisms of miR-16 in HSCs are not understood. In this study, The miRNA RNAi technique was used to analyze the effects of miR-16 on biological properties of HSCs in vitro. The lentiviral vector encoding miR-16 was constructed and transfected. Furthermore, the expression level of miR-16 was measured by real-time PCR. Cellular growth and proliferation capacity were assayed using the cell counting kit-8 (CCK-8). The apoptosis rate and cell-cycle distribution were measured by flow cytometry. Cell morphological characteristics were identified by phase-contrast microscopy, fluorescence microscopy and electron microscopy. The underlying mechanisms related to the changes in biological properties were assessed. The identity of the recombinant plasmid was confirmed by restriction endonuclease analysis and DNA sequencing. Virus titer was 10(8) > ifu/m. Restoring the intracellular miRNAs by miR-16 administration greatly reduced the expression levels of cyclin D1 (CD1). Cell-cycle arrest and typical features of apoptosis were detected in activated HSCs treated with pLV-miR-16. Our results indicate that transduction of miR-16 offers a feasible approach to significantly inhibit HSC proliferation and increase the apoptosis index. Thus, targeted transfer of miR-16 into HSC may be useful for the treatment of hepatic fibrosis.

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Molecular basis for calcium signaling in hepatic stellate cells

Cited by 30 publications

References 34 publications

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis

Effects of upregulated expression of microRNA-16 on biological properties of culture-activated hepatic stellate cells

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