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1 Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
2 Surgery, Vanderbilt University Medical Center, 801 Oxford House, Nashville, TN, 37232-4753, United States
3 Surgery, Vanderbilt University Medical Center, nashville, Tennessee, United States
4 Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States
5 Surgery, Vanderbilt University Medical Ce, Nashville, Tennessee, United States
6 Surgery, Vanderbilt University Medical Center , 1313 21st Avenue South, Nashville, Tennessee, 37205, United States
* To whom correspondence should be addressed. E-mail: ravi.chari{at}vanderbilt.edu.
Ischemia-reperfusion (I/R) injury is a commonly encountered clinical problem in liver surgery and transplantation. The pathogenesis of I/R injury is multi-factorial but mitochondrial Ca2+ overload plays a central role. We have previously defined a novel pathway for mitochondrial Ca2+ handling, and now further characterize this pathway and investigate a novel Ca2+ channel inhibitor, 2-APB, for preventing hepatic I/R injury. The effect of 2-APB on cellular and mitochondrial Ca2+ uptake was evaluated in vitro using 45Ca2+. Subsequently, 2-APB (2mg/kg) or vehicle was injected into the portal vein of anesthetized rats either prior to or following 1-hour inflow occlusion to 70% of the liver. After 3-hour reperfusion, liver injury was assessed enzymatically and histologically. HepG2 cells transfected with GFP-tagged cytochrome c were used to evaluate mitochondrial permeabiltiy. 2-APB dose-dependently blocked Ca2+ uptake in isolated liver mitochondria and reduced cellular Ca2+ accumulation in HepG2 cells. In vivo I/R increased liver enzymes 10-fold, and 2-APB prevented this when administered pre- or post-ischemia. 2-APB significantly reduced cellular damage determined by H&E and TUNEL staining of liver tissue. In vitro I/R caused a dissociation between cytochrome c and mitochondria in HepG2 cells that was prevented by administration of 2-APB. These data further establish the role of cellular Ca2+ uptake and subsequent mitochondrial Ca2+ overload in I/R injury and identify 2-APB as a novel pharmacologic inhibitor of liver I/R injury even when administered following a prolonged ischemic insult.
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