Attenuation of Endothelial Phosphatidylserine Exposure Decreases Ischemia-reperfusion INDUCED Changes in Microvascular Permeability

ABSTRACTIntroductionTranslocation of phosphatidylserine from the inner leaflet to the outer leaflet of the endothelial membrane via phospholipid scramblase-1 (PLSCR1) is an apoptotic signal responsible for the loss of endothelial barrier integrity after ischemia-reperfusion injury. We hypothesized that inhibiting phosphatidylserine expression on endothelial cells would attenuate ischemia-reperfusion (IRI) induced increases in hydraulic permeability (Lp).MethodsMesenteric hydraulic permeability (Lp) was measured in rat post-capillary mesenteric venules subjected to IRI via superior mesenteric artery (SMA) occlusion (45 minutes) and release (300 minutes) in conjunction with several inhibitors of phosphatidylserine exposure as follows: 1) inhibition of PLSCR1 translocation (DTE - dithioerythritol, n=3), 2) inhibition of PLSCR1 membrane trafficking (2-BP - 2-bromopalmitate, n=3), and 3) inhibition of ion exchange necessary for PLSCR1 function (DIDS - 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid, n=3). Under the same IRI conditions, rats were also administered targeted inhibitors of phosphatidylserine exposure including knockdown of phospholipid scramblase-1 (n=3) using RNA interference (RNAi), and as a potential therapeutic tool Diannexin, a selective phosphatidylserine blocker (n=3).ResultsDuring IRI net hydraulic permeability (Lp) increased by 80% (p

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