Bcl-2 upregulation after 3-nitropropionic acid preconditioning in warm rat liver ischemia.
We aimed to determine whether 3-nitropropionic acid (3-NPA) preconditioning protects rat livers against warm ischemia/reperfusion injury. We hypothesized that 3-NPA mediates its protective effects by Bcl-2 upregulation. Brown-Norway rats (200 g) were injected with 3-NPA (10 mg/kg intraperitoneally) 24 h before 90 min of selective warm in situ ischemia. In additional experiments, 30-day survival was studied after 90 min of warm liver ischemia and resection of nonischemic liver tissue. We demonstrate increased mRNA and protein levels of Bcl-2 by real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis in 3-NPA-pretreated rats. All treated animals survived, whereas all untreated rats died within 3 days after selective ischemia and resection of the nonischemic tissue. This corresponded well with a significant decrease of caspases 3 and 9 activity at 1 h of reperfusion after preconditioning with 3-NPA as compared with untreated rats. The histological sections showed protection of liver tissue after 3-NPA by reduction of apoptotic and oncotic tissue damage. Lipid peroxidation in liver tissue was reduced after 3-NPA preconditioning. We show that subtoxic doses of the mitochondrial toxin 3-NPA induces tolerance to warm liver ischemia in rats associated by synthesis of Bcl-2. Bcl-2 upregulation might protect against the postischemic burst of reactive oxygen species and therefore reduces apoptotic- and oncotic-related cell death.
Dünschede
Friedrich
F
Department of General and Abdominal Surgery, Johannes Gutenberg University Hospital, Mainz, Germany. Duenschede@ach.klinik.uni-mainz.de
Tybl
Elisabeth
E
Kiemer
Alexandra K
AK
Dutkowski
Philipp
P
Erbes
Kirsten
K
Kircher
Achim
A
Gockel
Ines
I
Zechner
Ulrich
U
Schad
Arno
A
Lang
Hauke
H
Junginger
Theodor
T
Kempski
Oliver
O
D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D008297:Male; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D052096:Warm Ischemia / Q000379:methods*
D009574:Nitro Compounds; D011422:Propionates; D019253:Proto-Oncogene Proteins c-bcl-2; D053148:Caspase 3; D053453:Caspase 9; C015392:3-nitropropionic acid