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Articles by Y Sun
Total Records ( 18 ) for Y Sun
  Z Zhang , Q Li , F Liu , Y Sun and J. Zhang

The aim of this study was to investigate the prevention of diet-induced obesity by a high safflower oil diet and adipocytic gene expression in mice. Forty 3-week-old C57BL/6 mice were randomly divided into three groups: control group (CON, 5% lard + 5% safflower oil), high lard group (LAR, 45% lard + 5% safflower oil), and high safflower oil group (SAF, 45% safflower oil + 5% lard). After 10 weeks, 10 mice of the LAR group were switched to high safflower oil diet (LAR–SAF). Ten weeks later, glucose tolerance tests were performed by intraperitoneal injection of glucose. Circulating levels of lipid and insulin were measured and white adipose tissues were taken for gene chip and reverse transcriptase–polymerase chain reaction analysis. The LAR group showed higher body weight, adiposity index, insulin, and lipids than the CON group (P < 0.05). The body weight in the LAR–SAF group decreased after dietary reversal. The plasma biochemical profiles decreased in the LAR–SAF and SAF groups (P < 0.05) compared with those of the LAR group. The blood glucose level of the LAR–SAF group was reduced during intraperitoneal glucose tolerance test compared with that of the LAR group. The LAR–SAF group had lower levels of Orexin and Ghrelin gene expression, whereas the level of PPAR gene expression was significantly enhanced compared with that of the LAR group. So, the SAF diet can alter adipocytic adiposity-related gene expression and result in effective amelioration of diet-induced obesity.

  H Jiang , Y Zhu , H Xu , Y Sun and Q. Li

Accumulating data suggested that hypoxia inducible factor (HIF)-1 plays an important role in the evolution and propagation of the inflammatory process. To characterize the activation of HIF-1 in rats with chronic obstructive pulmonary disease (COPD) and examine the possible role of nuclear factor (NF)-B in this process, rats were challenged by introtracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke. Pyrrolidine dithiocarbamate (PDTC) was administered via the oral route 1 h before LPS or cigarettes administration. Four weeks later, pulmonary function and histology were tested; bronchoalveolar lavage fluid (BALF) and arterial blood gases were assayed. Activation of pulmonary NF-B was assessed by quantitative PCR, immunoblot analysis, and electrophoretic mobility shift assay, respectively. Results showed that LPS and smog induced the characteristics of COPD seen in human. PDTC alleviated the development of COPD and the levels of cytokines in BALF of PDTC+COPD group were significantly decreased compared with that of COPD group. The activation of pulmonary NF-B was inhibited by PDTC and the accumulation of HIF-1 gene expression in the COPD group was attenuated by PDTC pretreatment. Furthermore, the mRNA levels of HIF-1 target genes heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) were parallel to the attenuation of HIF-1 by PDTC. These findings indicated that the activation of HIF-1 pathway via NF-B contributes to the development of COPD, and administration of NF-B inhibitor may attenuate the development of COPD.

  C Bian , F Zhang , F Wang , Z Ling , M Luo , H Wu , Y Sun , J Li , B Li , J Zhu , L Tang , Y Zhou , Q Shi , Y Ji , L Tian , G Lin , Y Fan , N Wang and B. Sun

DNA immunization is an efficient method for high-affinity monoclonal antibody generation. Here, we describe the generation of several high-quality monoclonal antibodies (mAbs) against retinol-binding protein 4 (RBP4), an important marker for kidney abnormality and dysfunction, with a combination method of DNA priming and protein boost. The mAbs generated could bind to RBP4 with high sensitivity and using these mAbs, an immunocolloidal gold fast test strip was constructed. The strip can give a result in <5 min and is very sensitive with a detection limit of about 1 ng/ml. A small-scale clinical test revealed that the result of this strip was well in accordance with that of an enzyme-labeled immunosorbent assay kit currently available on the market. Consequently, it could be useful for more convenient and faster RBP4 determination in the clinic.

  D. G Farwell , J. D Meier , J Park , Y Sun , H Coffman , B Poirier , J Phipps , S Tinling , D. J Enepekides and L. Marcu

Objective  To investigate the benefit of using time-resolved, laser-induced fluorescence spectroscopy for diagnosing malignant and premalignant lesions of the oral cavity.

Design  The carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) was applied to 1 cheek pouch of 19 hamsters. The contralateral pouch and the cheek pouches of 3 hamsters without DMBA exposure served as controls.

Setting  University of California, Davis.

Participants  Twenty-two golden/Syrian hamsters.

Intervention  A nitrogen pulse laser was used to induce tissue autofluorescence between the wavelengths of 360 and 650 nm.

Main Outcome Measures  Spectral intensities and time-domain measurements were obtained and compared with the histopathologic findings at each corresponding site.

Results  Spectral intensities and lifetime values at 3 spectral bands (SBs; SB1 = 380 ± 10 nm; SB2 = 460 ± 10 nm, and SB3 = 635 ± 10 nm) allowed for discrimination among healthy epithelium, dysplasia, carcinoma in situ, and invasive carcinoma. The lifetime values at SB2 were the most important when distinguishing the lesions using only time-resolved parameters. An algorithm combining spectral fluorescence parameters derived from both spectral and time-domain parameters (peak intensities, average fluorescence lifetimes, and the Laguerre coefficient [zero-order]) for healthy epithelium, dysplasia, carcinoma in situ, and invasive carcinoma provided the best diagnostic discrimination, with 100%, 100%, 69.2%, and 76.5% sensitivity and 100%, 92.2%, 97.1%, and 96.2% specificity, respectively.

Conclusions  The addition of time-resolved fluorescence-derived parameters significantly improves the capability of fluorescence spectroscopy–based diagnostics in the hamster buccal pouch. This technique provides a potential noninvasive diagnostic instrument for head and neck cancer.

  T. H Scheike , Y Sun , M. J Zhang and T. K. Jensen

We propose a semiparametric random effects model for multivariate competing risks data when the failures of a particular type are of interest. Under this model, the marginal cumulative incidence functions follow a generalized semiparametric additive model. The associations between the cause-specific failure times can be studied through dependence parameters of copula functions that are allowed to depend on cluster-level covariates. A cross-odds ratio-type measure is proposed to describe the associations between cause-specific failure times, and its relationship to the dependence parameters is explored. We develop a two-stage estimation procedure where the marginal models are estimated in the first stage and the dependence parameters are estimated in the second stage. The large sample properties of the proposed estimators are derived. The proposed procedures are applied to Danish twin data to model the cumulative incidence for the age of natural menopause and to investigate the association in the onset of natural menopause between monozygotic and dizygotic twins.

  L Wang , B Wu , Y Sun , T Xu , X Zhang , M Zhou and W. Jiang

Previous studies have indicated that protein kinase C (PKC) may enhance endothelial nitric oxide synthase (eNOS) activation, although the detailed mechanism(s) remains unclear. In this study, we investigated the roles of PKC isoforms in regulating propofol-induced eNOS activation in human umbilical vein endothelial cells (HUVECs).


We applied western blot (WB) analysis to investigate the effects of propofol on Ser1177 phosphorylation-dependent eNOS activation in HUVECs. Nitrite (NO2) accumulation was measured using the Griess assay. The phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway was examined by WB assay. Propofol-induced translocation of individual PKC isoforms in subcellular fractions in HUVECs was analysed using WB assay.


In HUVECs, protocol treatment (1–100 µM) for 10 min induced a concentration-dependent increase in phosphorylation of eNOS at Ser1177. The NO production was also increased accordingly. PKC inhibitors, bisindolylmaleimide I (0.1–1 µM), and staurosporine (20 and 100 nM), effectively blocked propofol-induced eNOS activation and NO production. Further analyses in fractionated endothelial lysate showed that short-term propofol treatment (50 µM) led to translocation of PKC-, PKC-, PKC-, PKC-, and PKC- from cytosolic to membrane fractions, which could also be inhibited by both PKC inhibitors. These data revealed that the differential redistribution of these isozymes is indispensable for propofol-induced eNOS activation. In addition, Akt was not phosphorylated in response to propofol at Ser473 or Thr308.


Propofol induces the Ser1177 phosphorylation-dependent eNOS activation through the drug-stimulated translocation of PKC isoforms to distinct intracellular sites in HUVECs, which is independent of PI3K/Akt-independent pathway.

  L Liu , Y. H Li , Y. B Niu , Y Sun , Z. J Guo , Q Li , C Li , J Feng , S. S Cao and Q. B. Mei

Evidence strongly supported a link between inflammation and cancer. Patients with colitis have high risk for development of colon cancer. Nuclear factor-kappa B (NF-B), partially induced by lipopolysaccharide (LPS) binding to Toll-like receptor (TLR) 4, is a vital molecule in supervising the transformation of colitis to colon cancer. It could be a good strategy to prevent colitis carcinogenesis for targeting LPS/TLR4/NF-B pathway. In the present study, we obtained an oligogalactan composed of five galacturonic acids from apple pectin and evaluated its protective efficacy on intestinal toxicities and carcinogenesis in a mouse model of colitis-associated colon cancer induced by 1,2-dimethylhydrazine and dextran sodium sulfate (DSS). The apple oligogalactan (AOG) was highly effective against intestinal toxicities and carcinogenesis and decreased the elevated levels of TLR4 and tumor necrosis factor- (TNF-) induced by inflammation in vivo in this model system. In vitro studies, AOG alone only slightly increased the levels of protein expression and messenger RNA of TLR4, phosphorylation of IB and production of TNF- in HT-29 cells. However, AOG significantly decreased the elevation of all the biomarkers induced by LPS when it was combined with LPS. The effect of AOG may be related to membrane internalization and redistribution of TLR4 from cell membrane to cytoplasm. AOG is active against inflammation and carcinogenesis through targeting LPS/TLR4/NF-B pathway. Both AOG and LPS are agonists of TLR4 for sharing the same ligand but AOG has a much lower intrinsic activity than that of LPS. AOG may be useful for treatment of colitis and prevention of carcinogenesis in the clinics.

  L Huang , C Zhu , Y Sun , G Xie , G. G Mackenzie , G Qiao , D Komninou and B. Rigas

Non-steroidal anti-inflammatory drugs such as sulindac are promising chemoprevention agents against colon cancer, but their weak potency and side effects limit their use for both chemoprevention and chemotherapy. Here, we evaluated the effect of a new sulindac derivative, phospho-sulindac or OXT-922, on the growth of human cancer cell lines and its mechanism of action. OXT-922 inhibited the growth of human cancer cell lines originating from colon, pancreas and breast ~11- to 30-fold more potently than sulindac. This effect was mediated by a strong cytokinetic effect. Compared with control, OXT-922 inhibited cell proliferation by up to 67%, induced apoptosis 4.1-fold over control and blocked the G1 to S cell cycle phase transition. OXT-922 suppressed the levels of cell cycle regulating proteins, including cyclins D1 and D3 and Cyclin-dependent kinases (CDK) 4 and 6. The levels of intracellular reactive oxygen species (ROS), especially those of mitochondrial $${\hbox{ O }}_{\hbox{ 2 }}^{\bullet -}$$, were markedly elevated (5.5-fold) in response to OXT-922. ROS collapsed the mitochondrial membrane potential and triggered apoptosis, which was largely abrogated by antioxidants. OXT-922 suppressed nuclear factor-kappaB activation and downregulated thioredoxin-1 expression. It also suppressed the production of prostaglandin E2 and decreased cyclooxygenase-1 expression. Similar to sulindac, OXT-922 enhanced spermidine/spermine N1-acetyltransferase activity, reduced the cellular polyamine content and synergized with difluoromethylornithine to inhibit cancer cell proliferation and induce apoptosis. Our results suggest that OXT-922 possesses promising anticancer properties and deserves further evaluation.

  Y Sun , G Hu , X Zhang and R. D. Minshall

Rationale: Oxidants are important signaling molecules known to increase endothelial permeability, although the mechanisms underlying permeability regulation are not clear.

Objective: To define the role of caveolin-1 in the mechanism of oxidant-induced pulmonary vascular hyperpermeability and edema formation.

Methods and Results: Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H2O2). Caveolin-1–deficient mice (cav-1–/–) were resistant to H2O2-induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H2O2 was completely rescued by expression of caveolin-1 in cav-1–/– mouse lung microvessels but was not restored by the phosphorylation-defective caveolin-1 mutant. The increase in caveolin-1 phosphorylation induced by H2O2 was dose-dependently coupled to both increased 125I-albumin transcytosis and decreased transendothelial electric resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H2O2 exposure resulted in the dissociation of vascular endothelial cadherin/β-catenin complexes and resultant endothelial barrier disruption.

Conclusions: Caveolin-1 phosphorylation–dependent signaling plays a crucial role in oxidative stress-induced pulmonary vascular hyperpermeability via transcellular and paracellular pathways. Thus, caveolin-1 phosphorylation may be an important therapeutic target for limiting oxidant-mediated vascular hyperpermeability, protein-rich edema formation, and acute lung injury.

  S Li , Y Sun , C. P Liang , E. B Thorp , S Han , A. W Jehle , V Saraswathi , B Pridgen , J. E Kanter , R Li , C. L Welch , A. H Hasty , K. E Bornfeldt , J. L Breslow , I Tabas and A. R. Tall

Rationale: The complications of atherosclerosis are a major cause of death and disability in type 2 diabetes. Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions.

Objective: To determine whether there is defective efferocytosis in a mouse model of obesity and atherosclerosis.

Methods and Results: We quantified efferocytosis in peritoneal macrophages and in atherosclerotic lesions of obese ob/ob or ob/ob;Ldlr–/– mice and littermate controls. Peritoneal macrophages from ob/ob and ob/ob;Ldlr–/– mice showed impaired efferocytosis, reflecting defective phosphatidylinositol 3-kinase activation during uptake of apoptotic cells. Membrane lipid composition of ob/ob and ob/ob;Ldlr–/– macrophages showed an increased content of saturated fatty acids (FAs) and decreased -3 FAs (eicosapentaenoic acid and docosahexaenoic acid) compared to controls. A similar defect in efferocytosis was induced by treating control macrophages with saturated free FA/BSA complexes, whereas the defect in ob/ob macrophages was reversed by treatment with eicosapentaenoic acid/BSA or by feeding ob/ob mice a fish oil diet rich in -3 FAs. There was also defective macrophage efferocytosis in atherosclerotic lesions of ob/ob;Ldlr–/– mice and this was reversed by a fish oil–rich diet.

Conclusions: The findings suggest that in obesity and type 2 diabetes elevated levels of saturated FAs and/or decreased levels of -3 FAs contribute to decreased macrophage efferocytosis. Beneficial effects of fish oil diets in atherosclerotic cardiovascular disease may involve improvements in macrophage function related to reversal of defective efferocytosis and could be particularly important in type 2 diabetes and obesity.

  A Lin , J Qian , X Li , X Yu , W Liu , Y Sun , N Chen , C Mei and for the Icodextrin National Multi center Cooperation Group

Background and objectives: While peritoneal dialysis with icodextrin is commonly used in patients with poor peritoneal membrane characteristics, the data on the usefulness of this solution in patients with lower transport characteristics are limited. The study was designed to compare icodextrin to glucose in Chinese prevalent peritoneal dialysis patients of different peritoneal transport characteristics (PET) categories.

Design, setting, participants, & measurements: This was a randomized, double-blind, perspective control study. Stable prevalent continuous ambulatory peritoneal dialysis (CAPD) patients were randomized to either 7.5% icodextrin (ICO) or 2.5% glucose (GLU) solution for 4 wk. Peritoneal membrane function was measured to define PET category in baseline. Creatinine clearance (Ccr), urea nitrogen clearance (CBUN), ultrafiltration (UF) during the long night dwell, dialysate, and metabolic biomarkers were measured at baseline, 2, and 4 wk. UF, Ccr, and CBUN were compared among different PET categories.

Results: A total of 201 CAPD patients were enrolled in the study. There were no baseline differences between the groups. Following 2 and 4 wk of therapy, Ccr, CBUN, and UF were all significantly higher in the ICO versus the GLU group. Additionally, switching to ICO resulted in a significant increase in UF in high, high-average, and low-average transporters as compared with baseline. The extent of increased UF was more obvious in higher transporters. Blood cholesterol level in the ICO group decreased significantly than that in the GLU group.

Conclusion: Compared with glucose-based solution, 7.5% icodextrin significantly improved UF and small solute clearance, even in patients with low-average peritoneal transport.

  A Takakura , L Contrino , X Zhou , J. V Bonventre , Y Sun , B. D Humphreys and J. Zhou

The ‘two-hit’ model is a widely accepted genetic mechanism for progressive cyst formation in autosomal dominant polycystic kidney disease. We have previously shown that adult inactivation of Pkd1 using the Mx1Cre+ allele causes a late onset of focal cystic disease. An explanation for the delayed appearance of cysts is the requirement for an additional independent factor, or ‘third hit’. Here we show that renal injury leads to massive cystic disease in the same mouse line. Cysts are labeled with a collecting duct/tubule marker, Lectin Dolichos biflorus Agglutinin, which correlates with the site of Cre-mediated recombination in the collecting system. 5-Bromo-2'-deoxyuridine labeling reveals that cyst-lining epithelial cells are comprised of regenerated cells in response to renal injury. These data demonstrate, for the first time, a role for polycystin-1 in kidney injury and repair and indicate that renal injury constitutes a ‘third hit’ resulting in rapid cyst formation in adulthood.

  X Wang , J Hao , Y Xie , Y Sun , B Hernandez , A. K Yamoah , M Prasad , Q Zhu , J. Q Feng and C. Qin

Mutations in FAM20C were recently identified as the cause of lethal osteosclerotic bone dysplasia, which highlighted the important role of this molecule in biomineralization. No systematic studies have been performed to evaluate the expression pattern of this relatively new molecule in the developmental processes of bone and tooth. In the present study, we analyzed in detail the expression profile of FAM20C during osteogenesis and odontogenesis using ISH and IHC approaches. The specimens analyzed were mouse tissues spanning embryonic day 13.5 (E13.5) to postnatal 8 weeks. The earliest presence of FAM20C was observed at E14.5. During osteogenesis, FAM20C mRNA was detected in the chondrocytes and osteoblasts of the long bone, whereas its protein was observed in the extracellular matrix (ECM) of bone and in the cytoplasm of the chondrocytes, osteoblasts, and osteocytes. During odontogenesis, FAM20C mRNA was detected in the ameloblasts, odontoblasts, cementoblasts, and periodontal ligament fibroblasts, whereas its protein was observed in the matrices of dentin, enamel, and alveolar bone and in the cytoplasm of the aforementioned cells. The temporospatial expression profile revealed in this study indicates that FAM20C is an ECM protein that may play an important role in controlling the mineralization of bone and tooth. (J Histochem Cytochem 58:957–967, 2010)

  Y Sun , S Ma , J Zhou , A. K Yamoah , J. Q Feng , R. J Hinton and C. Qin

The small integrin-binding ligand, N-linked glycoprotein (SIBLING) family is closely related to osteogenesis. Until recently, little was known about their existence in articular cartilage. In this study, we systematically evaluated the presence and distribution of four SIBLING family members in rat femoral head cartilage: dentin matrix protein 1 (DMP1), bone sialoprotein (BSP), osteopontin (OPN), and dentin sialophosphoprotein (DSPP). First, non-collagenous proteins were extracted and then separated by ion-exchange chromatography. Next, the protein extracts eluted by chromatography were analyzed by Stains-all staining and Western immunoblotting. IHC was used to assess the distribution of these four SIBLING family members in the femoral head cartilage. Both approaches showed that all the four SIBLING family members are expressed in the femoral head cartilage. IHC showed that SIBLING members are distributed in various locations throughout the articular cartilage. The NH2-terminal fragments of DMP1, BSP, and OPN are present in the cells and in the extracellular matrix, whereas the COOH-terminal fragment of DMP1 and the NH2-terminal fragment of DSPP are primarily intracellularly localized in the chondrocytes. The presence of the SIBLING family members in the rat femoral head cartilage suggests that they may play important roles in chondrogenesis. (J Histochem Cytochem 58:1033–1043, 2010)

  H Zhang , M Li , X Zheng , Y Sun , Z Wen and X. Zhao

In normal endometrium, stromal factors regulate the growth of epithelial cells. However, epithelial cells in endometriotic lesions display increased proliferation and decreased apoptosis. This work tested the hypothesis that in endometriosis stromal cells lose the ability to regulate survival signaling and cell growth in epithelial cells. Primary normal, endometriotic eutopic and ectopic epithelial cells were cultured in the presence of medium conditioned by normal, eutopic and ectopic endometriotic endometrial stromal cells. Endometriotic epithelial cells showed higher Survivin expression than normal epithelial cells. Conditioned medium (CM) from normal or eutopic endometriotic stromal cells significantly inhibited the Survivin expression and AKt phosphorylation in normal or eutopic endometriotic epithelial cells. However, CM from ectopic endometriotic stromal cells did not have an inhibitory effect on normal or ectopic endometriotic epithelial cells. Inhibition of AKt phosphorylation and Survivin expression in normal or eutopic endometriotic epithelial cells in the presence of stromal factors from normal or eutopic endometriotic stromal cells was enhanced by progesterone, whereas progesterone had little effect in the presence of stromal factors from ectopic endometriotic stromal cells. The inability of ectopic endometriotic stromal cells to regulated PI3K/AKt/Survivin signaling and mediate the progesterone response in endometriotic epithelial cells may facilitate epithelial cell proliferation in endometriosis and promote the survival of endometriotic lesions.

  M Li , Y Sun , J. M Simard , J. Y Wang and T. C. Chai

Overactive bladder syndrome (OAB) is an idiopathic condition characterized by urinary urgency and urge incontinence. Detrusor overactivity has been traditionally described as the physiologic mechanism for OAB. However, the bladder urothelium (BU) may also be involved in the pathophysiology. This study measured polyamine signaling and its downstream effects on membrane conductivity in bladder urothelial cells (BUC) obtained from asymptomatic and OAB subjects. Immunohistofluorescence was used to measure ornithine decarboxylase (ODC) expression in BU. BUC, cultured from BU biopsies, were used for electrophysiologic studies. dl--Difluoromethylornithine (DFMO), spermine, or spermidine was used to modulate polyamine signaling in BUC. Results showed ODC overexpression in OAB BU. In OAB BUC, whole cell and cell-attached configuration showed significantly decreased currents. Using inside-out patches, outward currents increased significantly, suggesting a cytoplasmic source of the outward current block in OAB BUC. In control BUC, outward currents were mediated by the large-conductance calcium-activated potassium (BK) channel due to calcium dose-dependence and block by iberiotoxin. Spermidine and spermine blocked the outward current in normal BUC in dose-dependent fashion. Conversely, DFMO significantly increased (P < 0.01) outward currents in OAB BUC both in cell-attached and in whole cell configuration. The outward currents in DFMO-treated-OAB BUC could be significantly reduced (P < 0.05) by adding back spermidine and spermine. These data suggest that polyamine signaling is upregulated in OAB urothelium and OAB BUC. Furthermore, polyamines in BUC block the BK channel. Targeting of bladder urothelial polyamine signaling may represent a novel approach for OAB treatment based on pathophysiologic mechanisms.

  K Watanabe , T Nagaoka , J. M Lee , C Bianco , M Gonzales , N. P Castro , M. C Rangel , K Sakamoto , Y Sun , R Callahan and D. S. Salomon

Cripto-1 associates with Notch1 in the endoplasmic reticulum and Golgi to enhance Notch1 localization to lipid rafts and its maturation.

  M. K Mirza , Y Sun , Y. D Zhao , H. H S.K. Potula , R. S Frey , S. M Vogel , A. B Malik and Y. Y. Zhao

Repair of the injured vascular intima requires a series of coordinated events that mediate both endothelial regeneration and reannealing of adherens junctions (AJs) to form a restrictive endothelial barrier. The forkhead transcription factor FoxM1 is essential for endothelial proliferation after vascular injury. However, little is known about mechanisms by which FoxM1 regulates endothelial barrier reannealing. Here, using a mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO) and primary cultures of ECs with small interfering RNA (siRNA)-mediated knockdown of FoxM1, we demonstrate a novel requisite role of FoxM1 in mediating endothelial AJ barrier repair through the transcriptional control of β-catenin. In the FoxM1 CKO lung vasculature, we observed persistent microvessel leakage characterized by impaired reannealing of endothelial AJs after endothelial injury. We also showed that FoxM1 directly regulated β-catenin transcription and that reexpression of β-catenin rescued the defective AJ barrier–reannealing phenotype of FoxM1-deficient ECs. Knockdown of β-catenin mimicked the phenotype of defective barrier recovery seen in FoxM1-deficient ECs. These data demonstrate that FoxM1 is required for reannealing of endothelial AJs in order to form a restrictive endothelial barrier through transcriptional control of β-catenin expression. Therefore, means of activating FoxM1-mediated endothelial repair represent a new therapeutic strategy for the treatment of inflammatory vascular diseases associated with persistent vascular barrier leakiness such as acute lung injury.

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