Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning

Cescon, Matteo; Carini, Rita; Grazi, Gian Luca; Caraceni, Paolo; Alchera, Elisa; Gasloli, G.; Ravaioli, Matteo; Tuci, F.; Imarisio, Chiara; Ponte, Caterina Dal; Pertosa, Anna Maria; Bernardi, Mauro; Pinna, Antonio; Albano, Emanuele

doi:10.1016/j.jhep.2008.11.016

Cited by 20 publications

(26 citation statements)

References 41 publications

(62 reference statements)

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“…Interestingly, JNK-1 − / − mice also show a decreased JNK-2 phosphorylation [25], a condition resembling our findings. The coupling of A 2a Rs with the PI3K/Akt signal pathway has been previously characterized in hepatocytes and involves direct PI3K activation through the interaction with inhibitory G α -proteins and Src [14] as well as the downmodulation of PI3K regulatory mechanisms involving PTEN (phosphatase and tensin homologue deleted on chromosome 10) [29]. We observed that PI3K/Aktmediated Ser 80 phosphorylation of MKK4/SEK1 is involved in CGS21680 protection against SA-induced lipotoxicity.…”

Section: Figure 5 Cgs21680 Treatment Prevents Hepatocyte Apoptosis Anmentioning

confidence: 56%

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

Imarisio¹,

Alchera²,

Sutti³

et al. 2012

Clinical Science

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NEFA (non-esterified 'free' fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A(2a) receptor) stimulation against lipotoxicity. The effects of the A(2a)R agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine] were evaluated 'in vitro' in liver cells exposed to SA (stearic acid) and 'in vivo' in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt-mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A(2a)R stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A(2a)R agonists as possible new therapeutic agents in preventing fatty liver progression to NASH.

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Section: Figure 5 Cgs21680 Treatment Prevents Hepatocyte Apoptosis Anmentioning

confidence: 56%

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

Imarisio¹,

Alchera²,

Sutti³

et al. 2012

Clinical Science

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“…Diacylglycerol kinase theta (DGKθ) and the phosphatase tensin-homologues-deleted from chromosome 10 (PTEN) which metabolize diacyglycerol and phosphatidylinositol, respectively, are inhibited during preconditioning to sustain activation of the diacylglycerol (DAG)-dependent PKC δ and ε and the PI3K-dependent signals. See text and Refs [21,25,27,28,32,35,37,43] represents an important pathway in the development of liver IP. Interestingly, PKB/AKT activation in connection with the development of tolerance to I/R was evident in rat hepatocytes and mouse livers [32,34] undergoing IP, as well as in preconditioned human liver grafts immediately after transplantation [35] .…”

Section: Signalling Pathways Involved In Adenosine and Atpinduced Hepmentioning

confidence: 99%

Molecular mechanisms of liver preconditioning

Alchera

Ponte²,

Imarisio³

et al. 2010

WJG

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Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic preconditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs, liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase, protein kinase C δ/ε and p38 MAP kinase, and transcription factors such as signal transducer and activator of transcription 3, nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery.

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“…The effect of ischemic preconditioning for 10 min on outcomes after LT was analyzed in 7 studies with a total of 334 participants [47,48,49,50,51,52,53], and showed improved short-term liver function by enhancement of AST and INR levels within the first days post-transplantation but had no effect on long-term transplant outcomes.…”

Section: Approaches For Preconditioning Organs In Order To Improve Trmentioning

confidence: 99%

Control of Ischemia-Reperfusion Injury in Liver Transplantation: Potentials for Increasing the Donor Pool

Kahn

Schemmer

2018

Visc Med

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Background: Organ shortage is a growing problem, with a rising number of organs being harvested from extended criteria donors, and this trend will further continue to increase as organ donors are getting older and have more comorbidities. Since this fact is immutable, efforts have been made to reduce the extent of ischemia-reperfusion injury (IRI) as well as of direct and indirect harvest-related graft injury which affects all organs in a more or less distinct way. Methods: In liver transplantation (LT), the activation of Kupffer cells during organ reperfusion, thus provoking microcirculatory disturbances, hypoxia, and endothelial cell injury, is one of the key mechanisms causing graft dysfunction. Multiple approaches have been taken in order to find efficient preconditioning methods by pharmacological pretreatment, controlled induction of ischemia, controlled denervation of donor organs, and reconditioning with machine perfusion to prevent IRI, whereas marginal organs (i.e. steatotic grafts) are especially vulnerable. Results: The above-mentioned approaches have been pursued in experimental and clinical settings. At this time point, however, there is not yet enough clinical evidence available to recommend any particular drug pretreatment or any other intervention for organ preconditioning prior to transplantation. Conclusion: The multifactorial pathophysiology in the setting of IRI in LT requires a multimodal therapeutic approach with the integration of pharmacological and technical means being applied to the donor, the organ per se, and the recipient. Currently, there is no consensus on standardized pretreatment of donor organs in order to improve the transplant outcome.

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Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning

Cited by 20 publications

References 41 publications

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats

Molecular mechanisms of liver preconditioning

Control of Ischemia-Reperfusion Injury in Liver Transplantation: Potentials for Increasing the Donor Pool

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