Background: S1P promotes endothelial barrier and is associated with HDL and albumin in blood. Results: HDL-S1P sustained barrier longer than albumin-S1P, reduced S1P receptor (S1P1) degradation, increased S1P1 cell surface and lipid raft levels, and persistently activated PI3K-Akt and eNOS. Conclusion: HDL-S1P persistently activates S1P-S1P1-PI3K-Akt-eNOS signaling. Significance: The findings highlight the basis for HDL-S1P as a mediator of sustained endothelial barrier.

BackgroundPerturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.MethodsHere we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.ResultsThe findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.ConclusionsWe provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.

Despite the emerging relevance of high-density lipoprotein (HDL) in the inflammatory cascade and vascular barrier integrity, HDL levels in children undergoing cardiac surgery are unexplored. As a measure of HDL levels, the HDL-cholesterol (HDL-C) in single-ventricle patients was quantified before and after the Fontan operation, and it was determined whether relationships existed between the duration and the type of postoperative pleural effusions. The study prospectively enrolled 12 children undergoing the Fontan operation. Plasma HDL-C levels were measured before and after cardiopulmonary bypass. The outcome variables of interest were the duration and type of chest tube drainage (chylous vs. nonchylous). The Kendall rank correlation coefficient and the Wilcoxon rank sum test were used. There were 11 complete observations. The median preoperative HDL-C level for all the subjects was 30 mg/dl (range, 24-53 mg/dl), and the median postcardiopulmonary bypass level was 21 mg/dl (range, 14-46 mg/dl) (p = 0.004). There was a tendency toward a moderate inverse correlation (-0.42) between the postcardiopulmonary bypass HDL-C level and the duration of chest tube drainage, but the result was not statistically significant (p = 0.07). In the chylous effusion group, the median postcardiopulmonary bypass HDL-C tended to be lower (16 vs. 23 mg/dl; p = 0.09). After the Fontan operation, the plasma HDL-C levels in children are significantly reduced. It is reasonable to conclude that the reduction in HDL-C reflects reduced plasma levels of HDL particles, which may have pertinent implications in postoperative pleural effusions given the antiinflammatory and endothelial barrier functions of HDL. KeywordsFontan; HDL-C; High-density lipoprotein-cholesterol Since the original description of the Fontan operation by Fontan and Baudet [8] in 1971, the procedure has undergone significant improvements in both the surgical and medical managements. These modifications have allowed a broad cross-section of patients with single-ventricle physiology to undergo successful Fontan palliation with excellent survival rates [1,13]. However, despite low mortality rates, patients who undergo the Fontan operation continue to remain at considerable risk for prolonged postoperative recovery complicated by persistent pleural effusions, ventricular dysfunction, arrhythmias, and protracted mechanical ventilation [18,21].Heart catheterization and echocardiographic evaluations are routinely performed before the Fontan operation in efforts to predict how the lungs and heart will interact. Yet, despite this practice, predicting the early postoperative course remains difficult, and it is becoming increasingly evident that catheterization hemodynamic data are not consistently associated with early postoperative outcomes [5,16]. This suggests the existence of other unexplored variables that place Fontan patients at risk for prolonged postoperative recovery despite acceptable hemodynamic criteria.In recent years, reductions in high-density lipoprotein (HDL) ...