Abstract
Recent studies have revealed that an intrinsic apoptotic signaling cascade is involved in vascular hyperpermeability and endothelial barrier dysfunction. Propofol (2,6-diisopropylphenol) has also been reported to inhibit apoptotic signaling by regulating mitochondrial permeability transition pore (mPTP) opening and caspase-3 activation. Here, we investigated whether propofol could alleviate burn serum-induced endothelial hyperpermeability through the inhibition of the intrinsic apoptotic signaling cascade. Rat lung microvascular endothelial cells (RLMVECs) were pretreated with propofol at various concentrations, followed by stimulation with burn serum, obtained from burn-injury rats. Monolayer permeability was determined by transendothelial electrical resistance. Mitochondrial release of cytochrome C was measured by ELISA. Bax and Bcl-2 expression and mitochondrial release of second mitochondrial-derived activator of caspases (smac) were detected by Western blotting. Caspase-3 activity was assessed by fluorometric assay; mitochondrial membrane potential (Δψm) was determined with JC-1 (a potential-sensitive fluorescent dye). Intracellular ATP content was assayed using a commercial kit, and reactive oxygen species (ROS) were measured by dichlorodihydrofluorescein diacetate (DCFH-DA). Burn serum significantly increased monolayer permeability (P<0.05), and this effect could be inhibited by propofol (P<0.05). Compared with a sham treatment group, intrinsic apoptotic signaling activation - indicated by Bax overexpression, Bcl-2 downregulation, Δψm reduction, decreased intracellular ATP level, increased cytosolic cytochrome C and smac, and caspase-3 activation - was observed in the vehicle group. Propofol not only attenuated these alterations (P<0.05 for all), but also significantly decreased burn-induced ROS production (P<0.05). Propofol attenuated burn-induced RLMVEC monolayer hyperpermeability by regulating the intrinsic apoptotic signaling pathway.
Highlights
Burns are a common form of traumatic injury and are associated with high mortality and morbidity rates [1,2]
These results revealed that propofol attenuated the burn serum-induced release of cytochrome C from mitochondria to cytosol
We investigated whether propofol could attenuate burn serum-induced endothelial hyperpermeability by inhibiting the activation of intrinsic apoptotic signaling
Summary
Burns are a common form of traumatic injury and are associated with high mortality and morbidity rates [1,2]. Resulting from endothelial barrier dysfunction and increased vascular hyperpermeability, blister and edema are considered to be classical signs in burn injury [3,4]. Some recent studies have suggested that the intrinsic apoptotic signaling cascade is involved in endothelial dysfunction, which is closely associated with vascular hyperpermeability [5,6]. In the intrinsic apoptotic pathway, activated mitochondria release cytochrome C and second mitochondrial-derived activator of caspases (smac), and caspase-3 is activated [7]. These mitochondrial factors are regulated by proapoptotic and antiapoptotic Bcl-2 family proteins, such as Bax/Bak and Bcl-2/Bcl-xL. Caspase-3 can cleave b-catenin resulting in the dissociation of the vascular endothelial (VE)-cadherin-bcatenin complex [8], which could induce microvascular hyperpermeability [9]
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