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Am J Physiol Heart Circ Physiol (February 16, 2007). doi:10.1152/ajpheart.01337.2006
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Submitted on December 7, 2006
Accepted on February 14, 2007

Apoptotic signaling induces hyperpermeability following hemorrhagic shock

Ed W Childs1*, Binu Tharakan2, Felicia A Hunter2, John H. Tinsley1, and Xiaobo Cao2

1 Surgery, Texas A & M University HSC College of Medicine and Scott and White Hospital, Temple, Texas, United States
2 Temple, Texas, United States; Surgery, Texas A & M University HSC College of Medicine and Scott and White Hospital, Temple, Texas, United States

* To whom correspondence should be addressed. E-mail: echilds{at}swmail.sw.org.

Hemorrhagic shock (HS) disrupts the endothelial cell barrier resulting in microvascular hyperpermeability. Recent studies have also demonstrated that activation of the apoptotic signaling cascade is involved in endothelial dysfunction, which may result in hyperpermeability. Here we report involvement of the mitochondrial "intrinsic" pathway in microvascular hyperpermeability following HS in rats. Hemorrhagic shock resulted in the activation of the mitochondrial intrinsic pathway evident by an increase in the pro-apoptotic Bcl-2 family member BAK, release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. This, along with the in vivo transfection of the pro-apoptotic peptide BAK (BH3), resulted in hyperpermeability as visualized by intravital microscopy, release of mitochondrial cytochrome c into the cytoplasm, and activation of caspase-3. Conversely, transfection of the BAK (BH3) mutant had no effect on hyperpermeability. Together, these results demonstrate involvement of the mitochondrial intrinsic apoptotic pathway in HS-induced hyperpermeability and that the attenuation of this pathway may provide an alternative strategy in preserving vascular barrier integrity.




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