RGD Reference Report - Intermittent ischemia reduces warm hypoxia-reoxygenation-induced JNK(1)/SAPK(1) activation and apoptosis in rat hepatocytes. - Rat Genome Database

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Intermittent ischemia reduces warm hypoxia-reoxygenation-induced JNK(1)/SAPK(1) activation and apoptosis in rat hepatocytes.

Authors: Crenesse, D  Laurens, M  Gugenheim, J  Heurteaux, C  Cursio, R  Rossi, B  Schmid-Alliana, A 
Citation: Crenesse D, etal., Hepatology. 2001 Nov;34(5):972-8.
RGD ID: 10412680
Pubmed: PMID:11679968   (View Abstract at PubMed)
DOI: DOI:10.1053/jhep.2001.28709   (Journal Full-text)

Prolonged liver ischemia followed by reperfusion (I/R) causes functional and structural damage to liver cells, resulting in necrosis and apoptosis. c-jun N-terminal kinase 1/stress-activated protein kinase 1 (JNK(1)/SAPK(1)) is activated during I/R and participates in the onset of the apoptosis program. Excessive blood loss during surgery can hinder postoperative recovery. Intermittent portal triad clamping (PTC) is better tolerated than prolonged continuous ischemia. This study was designed to demonstrate that intermittent ischemia could improve postischemic survival rates by a decrease of JNK(1)/SAPK(1) and caspase 3 activation, which were involved in the apoptosis process. Rats were subjected to intermittent 1-hour ischemia (15-minute ischemia/5-minute reperfusion, 4 times), followed by 220-minute reperfusion, or to continuous ischemia (1 hour), followed by 240-minute reperfusion. Mortality rates were assessed on day 7. Serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase levels (LDH) were measured 6 hours after ischemia. This study was completed in primary cultured isolated rat hepatocytes, subjected to the same continuous or intermittent hypoxic conditions. The activation status of JNK(1)/SAPK(1) was evaluated by immunoprecipitation or Western blotting experiments. Apoptosis was assessed by measuring caspase activation and by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) reaction. Eighty percent of the intermittent-ischemia group was alive 7 days after surgery and serum enzyme levels were significantly decreased. Intermittent hypoxia or ischemia did not lead to JNK(1)/SAPK(1) activation, but at least 3 hypoxia-reoxygenation (H/R) sets were necessary to inhibit kinase activation. Consequently, caspase 3 activation and apoptosis were dramatically reduced. Intermittent ischemia is a powerful, protective way to reduce I/R damage of the liver, by reduction of JNK(1)/SAPK(1) activation associated with a down-regulation of caspase 3 activity, which leads to inhibition of hepatocyte apoptosis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Liver Reperfusion Injury  ISOMapk8 (Rattus norvegicus)10412680; 10412680protein:increased activity:liver:RGD 
Liver Reperfusion Injury  IEP 10412680protein:increased activity:liver:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mapk8  (mitogen-activated protein kinase 8)

Genes (Mus musculus)
Mapk8  (mitogen-activated protein kinase 8)

Genes (Homo sapiens)
MAPK8  (mitogen-activated protein kinase 8)


Additional Information