Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion.
The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1alpha and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to approximately 70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 micromol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1.
Zhong
Zhi
Z
Dept. of Pharmaceutical Sciences, Medical Univ. of South Carolina, 280 Calhoun St., PO Box 250140, Charleston, SC 29425, USA. zhong@musc.edu
Ramshesh
Venkat K
VK
Rehman
Hasibur
H
Currin
Robert T
RT
Sridharan
Vijayalakshmi
V
Theruvath
Tom P
TP
Kim
Insil
I
Wright
Gary L
GL
Lemasters
John J
JJ
D000818:Animals; D051547:Heme Oxygenase-1 / Q000378:metabolism; D062385:Hydroxybenzoates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology*; D000083162:Mitochondrial Permeability Transition Pore; D010100:Oxygen / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D011524:Protoporphyrins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
C497443:Hif1a protein, mouse; D062385:Hydroxybenzoates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008665:Metalloporphyrins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011524:Protoporphyrins; C018063:ethyl protocatechuate; C032628:tin protoporphyrin IX; D011393:Procollagen-Proline Dioxygenase; D051547:Heme Oxygenase-1; D010100:Oxygen
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