• Binu Tharakan, Juliet G Holder-Haynes, Felicia A Hunter, W Roy Smythe, and Ed W Childs.
• Department of Surgery, Texas A&M University System Health Science Center College of Medicine, Scott and White Memorial Hospital, Temple, Texas 76508, USA.
• J Trauma. 2009 Apr 1;66(4):1033-9.

BackgroundHemorrhagic shock (HS) is associated with the activation of caspase-dependent or -independent apoptotic signaling pathways, disruption of endothelial cell adherens junctions, and vascular hyperpermeability. Recent studies have suggested that the vascular hyperpermeability observed after HS is associated with activation of the intrinsic apoptotic signaling cascade resulting in caspase-mediated cleavage of endothelial cell adherens proteins and subsequent cell-cell detachment. We hypothesized that cyclosporine A (CsA) would attenuate vascular hyperpermeability after HS by protecting mitochondrial transition pores and thereby preventing the activation of caspase-mediated apoptotic signaling. The objective of this study was to determine the effect of CsA on, HS-induced hyperpermeability, mitochondrial membrane depolarization, mitochondrial release of cytochrome c, and caspase 3 activation.MethodsHS was induced in Sprague-Dawley rats by withdrawing blood to reduce the mean arterial pressure to 40 mm Hg for 60 minutes. CsA (10 microL/mL) was given 10 minutes before the shock period. The mesenteric postcapillary venules of the proximal ileum were monitored for permeability changes using intravital microscopy. The changes in mitochondrial transmembrane potential were determined using the cationic dye JC-1. Mitochondrial release of cytochrome c in to the cytosol was detected using ELISA. Caspase-3 activity was measured using a fluorometric assay.ResultsHS induced vascular hyperpermeability, release of cytochrome c, and activation of caspase-3 (p < 0.05). CsA (10 microL/mL) attenuated HS-induced hyperpermeability (p < 0.05) and prevented HS-induced decrease in mitochondrial transmembrane potential. CsA treatment decreased the HS-induced rise in cytosolic cytochrome c levels and caspase-3 activity (p < 0.05).ConclusionsThese findings demonstrate that CsA protects mitochondrial permeability transition pores to prevent HS-induced release of cytochrome c and caspase-3 activation.

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