1. Negative regulation of diacylglycerol kinase θ mediates adenosine-dependent hepatocyte preconditioning
- Author
-
Emanuele Albano, Mariapaola Nitti, Andrea Graziani, W J van Blitterswijk, M. Gaggianesi, C. Imarisio, R. Carini, Gianluca Baldanzi, C. Dal Ponte, E. Alchera, Cinzia Domenicotti, Baldanzi G., Alchera E., Imarisio C., Gaggianesi M., Dal Ponte C., Nitti M., Domenicotti C., Van Blitterswijk W.J., Albano E., Graziani A., Carini R., Baldanzi, G, Alchera, E, Imarisio, C, Gaggianesi, M, Dal Ponte, C, Nitti, M, Domenicotti, C, van Blitterswijk, Wj, Albano, E, Graziani, Andrea, and Carini, R.
- Subjects
Male ,Diacylglycerol Kinase ,medicine.medical_specialty ,Adenosine ,Receptor, Adenosine A2A ,p38 mitogen-activated protein kinases ,Biology ,Quinazolinone ,chemistry.chemical_compound ,Piperidine ,cytoprotection ,Piperidines ,Downregulation and upregulation ,Diacylglycerol kinase theta ,Internal medicine ,medicine ,Enzyme Inhibitor ,hepatocytes, adenosine, RhoA, hypoxia, cytoprotection ,Animals ,Hepatocyte ,Enzyme Inhibitors ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Protein kinase C ,Quinazolinones ,Diacylglycerol kinase ,Cell Death ,Animal ,hypoxia ,Kinase ,Receptors, Purinergic P1 ,RhoA ,Cell Biology ,Phosphatidic acid ,Cell Hypoxia ,Rats ,Cell biology ,Endocrinology ,chemistry ,Hepatocytes ,Rat ,rhoA GTP-Binding Protein ,medicine.drug - Abstract
In liver ischemic preconditioning (IP), stimulation of adenosine A2a receptors (A2aR) prevents ischemia/reperfusion injury by promoting diacylglycerol-mediated activation of protein kinase C (PKC). By concerting diacylglycerol to phosphatidic acid, diacylglycerol kinases (DGKs) act as terminator of diacylglycerol signalling. This study investigates the role of DGK in the development of hepatocyte IP. DGK activity and cell viability were evaluated in isolated rat hepatocytes preconditioned by 10 min hypoxia followed by 10 min re-oxygenation or by the treatment with the A2aR agonist, CGS21680, and subsequently exposed to prolonged hypoxia. We observed that after IP or A2aR activation, a decrease in DGK activity was associated with the onset of hepatocyte tolerance to hypoxia. CGS21680-induced stimulation of A2aR specifically inhibited DGK isoform θ by activating RhoA-GTPase. Consistently, both siRNA-mediated downregulation of DGK θ and hepatocyte pretreatment with the DGK inhibitor R59949 induced cell tolerance to hypoxia. The pharmacological inhibition of DGK was associated with the diacylglycerol-dependent activation of PKC δ and ε and of their downstream target p38 MAPK. In conclusion, we unveil a novel signalling pathway contributing to the onset of hepatocyte preconditioning, which through RhoA-GTPase, couples A2aR to the downregulation of DGK. Such an inhibition is essential for the sustained accumulation of diacylglycerol required for triggering PKC-mediated survival signals. © 2010 Macmillan Publishers Limited All rights reserved.
- Published
- 2010
- Full Text
- View/download PDF