Article ; Online: Protein kinase A signals apoptotic activation in glucose-deprived hepatocytes: participation of reactive oxygen species.
Apoptosis : an international journal on programmed cell death
2012 Volume 17, Issue 5, Page(s) 475–491
Abstract: Glucose deprivation entails oxidative stress and apoptosis in diverse cell types. Liver tissue shows high tolerance to nutritional stress, however regulation of survival in normal hepatocytes subjected to glucose restriction is unclear. We assessed the ... ...
Abstract | Glucose deprivation entails oxidative stress and apoptosis in diverse cell types. Liver tissue shows high tolerance to nutritional stress, however regulation of survival in normal hepatocytes subjected to glucose restriction is unclear. We assessed the survival response of cultured hepatocytes subjected to glucose deprivation and analyzed the putative participation of protein kinase A (PKA) in this response. Six hours glucose deprivation induced a PKA dependent activation of apoptosis in cultured hepatocytes, without having an impact on non apoptotic death. Apoptotic activation associated to glucose restriction was secondary to an imbalance in cellular reactive oxygen species (ROS). In this condition, PKA inhibition led to an early prevention in mitochondrial ROS production and a late increase in scavenging enzymes transcript levels. These results supported the hypothesis that PKA could modulate glucose deprivation induced apoptotic activation by conditioning mitochondrial ROS production during glucose fasting. We presented additional evidence sustaining this model: First, glucose withdrawal led to a 95% increase in mitochondrial cAMP levels in cultured hepatocytes; second, activation of PKA significantly augmented hepatic mitochondrial ROS generation, whereas PKA inhibition elicited the opposite effect. Mitochondrial PKA signaling, previously proposed as an autonomic pathway adjusting respiration rate, emerges as a mechanism of controlling cell survival during glucose restriction. |
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MeSH term(s) | Animals ; Apoptosis ; Caspase 3/metabolism ; Catalase/genetics ; Catalase/metabolism ; Cell Survival ; Cells, Cultured ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cytochromes c/metabolism ; Cytosol/metabolism ; Glucose/deficiency ; Hepatocytes/enzymology ; Hepatocytes/physiology ; Isoquinolines/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Male ; Mitochondria/metabolism ; Oxidative Stress ; Protein Transport ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Sulfonamides/pharmacology ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; bcl-2-Associated X Protein/metabolism |
Chemical Substances | Bax protein, rat ; Isoquinolines ; Reactive Oxygen Species ; Sulfonamides ; bcl-2-Associated X Protein ; Cytochromes c (9007-43-6) ; Cyclic AMP (E0399OZS9N) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Catalase (EC 1.11.1.6) ; Sod1 protein, rat (EC 1.15.1.1) ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Casp3 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Glucose (IY9XDZ35W2) ; N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (M876330O56) |
Language | English |
Publishing date | 2012-05 |
Publishing country | Netherlands |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1452360-7 |
ISSN | 1573-675X ; 1360-8185 |
ISSN (online) | 1573-675X |
ISSN | 1360-8185 |
DOI | 10.1007/s10495-012-0697-2 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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