Caveolin-1 Expression Research Articles

Increased expression of Caveolin-1 in both of the vitreous and the proliferating membranes among the patients with proliferative diabetic retinopathy

Increased expression of Caveolin-1 in both of the vitreous and the proliferating membranes among the patients with proliferative diabetic retinopathy

Expression of Amyloid Precursor Protein, Caveolin-1, Alpha-, Beta-, and Gamma-Secretases in Penumbra Cells after Photothrombotic Stroke and Evaluation of Neuroprotective Effect of Secretase and Caveolin-1 Inhibitors.

Our studies reveal changes in the expression of the main participants in the processing of amyloid precursor protein (APP) in neurons and astrocytes after photothrombotic stroke (PTS). Here we show the increase in the level of N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells at 24 h after PTS and their co-immunoprecipitation with caveolin-1. The ADAM10 α-secretase level decreased in the rat brain cortex on the first day after PTS. Levels of γ-secretase complex proteins presenilin-1 and nicastrin were increased in astrocytes, but not in neurons, in the penumbra after PTS. Inhibitory analysis showed that these changes lead to neuronal death and activation of astrocytes in the early recovery period after PTS. The caveolin-1 inhibitor daidzein shifted APP processing towards Aβ synthesis, which caused astroglial activation. γ-secretase inhibitor DAPT down-regulated glial fibrillary acidic protein (GFAP) in astrocytes, prevented mouse cerebral cortex cells from PTS-induced apoptosis, and reduced the infarction volume. Thus, new generation γ-secretase inhibitors may be considered as potential agents for the treatment of stroke.

The Immunohistochemical Expression of the Von Willebrand Factor: A Potential Tool to Predict Kidney Allograft Outcomes.

Few reports assessed endothelial activation biomarkers in kidney allograft biopsies using immunohistochemistry. This retrospective cohort study evaluated the association between posttransplant outcomes and the immunohistochemistry expression of Caveolin-1, Von Willebrand Factor (Vwf), and T-Cadherin in for-cause biopsies diagnosed as interstitial fibrosis and tubular atrophy of unknown etiology. Samples with antibody-mediated changes were excluded. The patients were followed for 3 years after the biopsy or until graft loss/death. Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Caveolin-1 and T-Cadherin were not associated with graft loss. Vwf had good accuracy in predicting graft failure (AUC 0.637, 95% CI 0.486 to 0.788 P =0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf >10%) was associated with reduced death-censored graft survival (58.2% vs. 85.4% P =0.006), and this result was also observed in the subgroup presenting mild interstitial fibrosis (ci=1) (65.7% vs. 88.6% P =0.033). The multivariate analysis showed that Vwf >10% was an independent risk factor for graft loss (HR=2.88, 95% CI 1.03 to 8.02 P =0.043). In conclusion, Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with interstitial fibrosis and tubular atrophy of unknown etiology, probably reflecting immune endothelial activation.

Caveolin-1 accelerates hypoxia-induced endothelial dysfunction in high-altitude cerebral edema

BackgroundHigh-altitude cerebral edema (HACE) is a serious and potentially fatal brain injury that is caused by acute hypobaric hypoxia (HH) exposure. Vasogenic edema is the main pathological factor of this condition. Hypoxia-induced disruptions of tight junctions in the endothelium trigger blood‒brain barrier (BBB) damage and induce vasogenic edema. Nuclear respiratory factor 1 (NRF1) acts as a major regulator of hypoxia-induced endothelial cell injury, and caveolin-1 (CAV-1) is upregulated as its downstream gene in hypoxic endothelial cells. This study aimed to investigate whether CAV-1 is involved in HACE progression and the underlying mechanism.MethodsC57BL/6 mice were exposed to HH (7600 m above sea level) for 24 h, and BBB injury was assessed by brain water content, Evans blue staining and FITC-dextran leakage. Immunofluorescence, transmission electron microscope, transendothelial electrical resistance (TEER), transcytosis assays, and western blotting were performed to confirm the role and underlying mechanism of CAV-1 in the disruption of tight junctions and BBB permeability. Mice or bEnd.3 cells were pretreated with MβCD, a specific blocker of CAV-1, and the effect of CAV-1 on claudin-5 internalization under hypoxic conditions was detected by immunofluorescence, western blotting, and TEER. The expression of NRF1 was knocked down, and the regulation of CAV-1 by NRF1 under hypoxic conditions was examined by qPCR, western blotting, and immunofluorescence.ResultsThe BBB was severely damaged and was accompanied by a significant loss of vascular tight junction proteins in HACE mice. CAV-1 was significantly upregulated in endothelial cells, and claudin-5 explicitly colocalized with CAV-1. During the in vitro experiments, hypoxia increased cell permeability, CAV-1 expression, and claudin-5 internalization and downregulated tight junction proteins. Simultaneously, hypoxia induced the upregulation of CAV-1 by activating NRF1. Blocking CAV-1-mediated intracellular transport improved the integrity of TJs in hypoxic endothelial cells and effectively inhibited the increase in BBB permeability and brain water content in HH animals.ConclusionsHypoxia upregulated CAV-1 transcription via the activation of NRF1 in endothelial cells, thus inducing the internalization and autophagic degradation of claudin-5. These effects lead to the destruction of the BBB and trigger HACE. Therefore, CAV-1 may be a potential therapeutic target for HACE.E5r9nDKChFa7F_nrUkRwh3Video abstract

Caveolin-1 and Tight Junction Expression in Human Intestine as a Susceptibility Marker of Necrotizing Enterocolitis

INTRODUCTION: Necrotizing enterocolitis (NEC) is a devastating disease of prematurity. NEC has been associated with increased intestinal epithelium permeability due to dysregulation of tight junction (TJ) proteins. Caveolin-1 is a ubiquitous membrane protein that is involved in cellular membrane maintenance by aiding in TJ assembly. We hypothesize that baseline levels of caveolin-1 differ in patients with NEC when compared to patients without NEC. METHODS: Human intestinal tissue was collected from patient samples during the time of operation. Patients were all preterm (<37 weeks) infants who underwent exploratory laparotomy for either NEC or non-NEC sources. University of Oklahoma Health Sciences Center IRB approval (#11611) and informed consent were obtained. Specimens were collected, deidentified, and stored. Specimens were paraffin embedded, stained, and imaged by immunofluorescence. Western blot analysis was performed on protein isolates. RESULTS: Infant intestinal tissue demonstrated a relative decreased expression of epithelial caveolin-1 in NEC tissues compared with controls. A nuclear stain (4′,6-diamidino-2-phenylindole) was used in conjunction with anti–caveolin-1 Ab to visualize caveolin expression in the intestinal mucosa. There is an increased concentration of caveolin-1 in patients without history of NEC (Fig. 1a). Western blot of intestinal tissue also revealed diminished caveolin-1 protein in patients with NEC (Fig. 1b). These data correlate with a decrease in the TJ occluding in patients with NEC (Fig. 1c).Figure 1CONCLUSION: We conclude that decreased caveolin-1 levels in intestinal epithelium may increase susceptibility to the development of necrotizing enterocolitis. This may be caused by a decrease intestinal TJ assembly and increased permeability of the intestinal epithelium.

Caveolin-1, GATA-3, and Ki67 expressions and their correlation with pathological findings in canine bladder urothelial carcinoma.

The bladder urothelial carcinoma (UC) represents ~2% of malignant neoplasms in dogs and is a therapeutic challenge in veterinary medicine. Although it is considered the most common bladder cancer in dogs, few previous studies have investigated different markers that correlate with clinical and pathological parameters. Therefore, this study aimed to evaluate Caveolin-1, GATA-3, and Ki67 immunostaining in canine UC samples to evaluate their correlations with histopathological variables. Thirty tumor samples were obtained, and Caveolin-1, GATA-3, and Ki67 expression was assessed by immunohistochemistry and associated with pathological factors by univariate and multivariate analyses. Among the histopathological findings, lymphatic invasion was identified in 53.33% of the tumors, and the mean mitotic count (MC) was 31.82 ± 26.26. Caveolin-1 showed mild-to-high cytoplasmic expression in neoplastic cells, whereas GATA-3 showed mild-to-high nuclear expression. The Ki67 expression revealed a mean of 24.14 ± 16.88% positive cells. In the univariate analysis, no association was found between each marker and the pathological findings. On the other hand, in multivariate analysis, we identified a positive correlation between GATA-3 and MC and a negative correlation between Caveolin-1 and MC. Moreover, lymphatic invasion was positively correlated with histological type and grade, and negatively correlated with MC. In addition, the histological type was positively correlated with the histological grade. Overall, our results indicate that Caveolin-1 and GATA-3 expression could be promising markers for bladder UC aggressiveness.

Hypoxia-induced pulmonary hypertension upregulates eNOS and TGF-β contributing to sex-linked differences in BMPR2 +/R899X mutant mice.

Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) have been largely implicated in the pathogenesis of pulmonary arterial hypertension (PAH); a life-threatening cardiopulmonary disease. Although the incident of PAH is about three times higher in females, males with PAH usually have a worse prognosis, which seems to be dependent on estrogen-associated cardiac and vascular protection. Here, we evaluated whether hypoxia-induced pulmonary hypertension (PH) in humanized BMPR2+/R899X loss-of-function mutant mice contributes to sex-associated differences observed in PAH by altering eNOS expression and inducing expansion of hyperactivated TGF-β-producing pulmonary myofibroblasts. To test this hypothesis, male and female wild-type (WT) and BMPR2+/R899X mutant mice were kept under hypoxic or normoxic conditions for 4 weeks, and then right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) were measured. Chronic hypoxia exposure elevated RVSP, inducing RVH in both groups, with a greater effect in BMPR2+/R899X female mice. Lung histology revealed no differences in vessel thickness/area between sexes, suggesting RVSP differences in this model are unlikely to be in response to sex-dependent vascular narrowing. On the other hand, hypoxia exposure increased vascular collagen deposition, the number of TGF-β-associated α-SMA-positive microvessels, and eNOS expression, whereas it also reduced caveolin-1 expression in the lungs of BMPR2+/R899X females compared to males. Taken together, this brief report reveals elevated myofibroblast-derived TGF-β and eNOS-derived oxidants contribute to pulmonary microvascular muscularization and sex-linked differences in incidence, severity, and outcome of PAH.

Postprandial triglyceride-rich lipoproteins promote the adipogenic differentiation of adipose-derived mesenchymal stem cells via the LRP1/caveolin-1/AKT1 pathway

Diet-induced obesity (OB) is usually accompanied by hypertriglyceridemia, which is characterized by the accumulation of triglyceride (TG)-rich lipoprotein (TRL) particles in the circulation. We previously found that postprandial TRL combined with insulin induced the adipogenic differentiation of 3T3-L1 preadipocytes, which may represent a key mechanism underlying obesity. However, the specific mechanism and signaling pathway involved in this process remain to be fully elucidated. In this study, we found that, in the postprandial state, patients with obesity had significantly higher levels of TG and remnant cholesterol (RC) than normal-weight controls. In vitro, we found that postprandial TRL, together with insulin, promoted the adipogenic differentiation of adipose-derived mesenchymal stem cells (AMSCs), as evidenced by the increased expression of lipogenesis-related genes and their protein products, including low-density lipoprotein related protein 1 (LRP1). Besides, caveolin-1 (Cav-1) expression was also significantly upregulated under this condition. Cav-1 and LRP1 were observed to interact, and then led to the activation of the PI3K/AKT1 signaling pathway. Meanwhile, the inhibition of LRP1 or Cav-1 significantly attenuated the adipogenic differentiation of AMSCs and downregulated AKT1 phosphorylation levels. Moreover, treatment with a selective AKT1 inhibitor significantly suppressed postprandial TRL and insulin-induced adipogenesis in AMSCs. Combined, our results demonstrated that, in association with insulin, postprandial TRL can promote the adipogenic differentiation of AMSCs in a manner that is dependent on the LRP1/Cav-1-mediated activation of the PI3K/AKT1 signaling pathway. Our findings indicated that a postprandial increase in TRL content is a critical factor in the pathogenesis of hypertriglyceridemia and diet-induced obesity.

Crucial Function of Caveolin-1 in Deoxynivalenol-Induced Enterotoxicity by Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis.

Deoxynivalenol (DON) is one of the most pervasive contaminating mycotoxins in grain, and exposure to DON is known to cause acute and chronic intestinal damage. As the gut is the most important target organ of DON, it is essential to identify the pivotal molecules involved in DON-induced enterotoxicity as well as the potential regulatory mechanisms. In the present study, we found that DON treatment dramatically decreased the jejunal villus height and increased the crypt depth in mice. DON exposure induced oxidative stress and NLRP3 inflammasome activation while increasing the levels of pyroptosis-related factors GSDMD, ASC, Caspase-1 P20, and IL-1β and inflammatory cytokines IL-18, TNF-α, and IL-6. In vitro, 0.5-2 μM DON caused cytotoxicity and oxidative stress, as well as NLRP3-mediated pyroptosis in IPEC-J2 cells. Furthermore, DON treatment substantially improved the expression of Caveolin-1 (Cav-1) in vitro and in vivo. Interestingly, Cav-1 knockdown effectively attenuated DON-induced oxidative stress and NLRP3-mediated pyroptosis in IPEC-J2 cells. Meanwhile, treatment with the antioxidant NAC significantly alleviated DON-induced cytotoxicity and pyroptosis in IPEC-J2 cells. Likewise, after inhibiting NLRP3 inflammasome activation with the inhibitor MCC950, DON-induced cytotoxicity, pyroptosis, and inflammatory response were attenuated. However, NLRP3 inhibition did not affect Cav-1 expression. In conclusion, our study demonstrated that pyroptosis may be an underlying mechanism in DON-induced intestinal injury, and Cav-1 plays a pivotal role in DON-induced pyroptosis via regulating oxidative stress, which suggests a novel strategy to overcome DON-induced enterotoxicity.

SZ168 treats LPS-induced acute lung injury by inhibiting the activation of NF-κB and MAPKs pathways

BackgroundThis study aimed to elucidate the effect and underlying molecular mechanisms of SZ168 (Podoplanin (PDPN) monoclonal antibody) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and LPS-induced MH-S cells. MethodsThe survival rate was calculated by recording the death of mice in each group. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)− 6 and tumor necrosis factor-alpha (TNF-α) in blood and bronchoalveolar lavage fluid (BALF) of mice. Hematoxylin-eosin (H&E) staining were performed to evaluate the pathological changes in pulmonary tissues. Additionally, the phagocytosis of cells was tested by flow cytometry, and the expression levels of caveolin-1 (CAV-1) and Occludin proteins in lung tissue and the expression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway-related proteins in MH-S cells were determined by western blot. ResultsSZ168 significantly improved the survival rate of ALI mice. Briefly speaking, SZ168 protected pulmonary vascular permeability, reduced the level of pro-inflammatory cytokines, improved the pathological changes of lung tissue, reduced the infiltration of inflammatory cells, increased CAV-1 and Occludin protein expression, and then effectively relieved lung injury. In addition, SZ168 could significantly reduce the phagocytic ability of LPS-induced MH-S cells and inhibit the expression of hospho-extracellular regulated protein kinases (p-ERK), Phospho-Jun N-terminal kinase (p-JNK), Phospho-NF-κB p65 (p-p65) and Phospho-IkappaB-alpha (p-IκBα). ConclusionSZ168 can treat ALI by inhibiting the activation of NF-κB and MAPK signaling pathways and restoring tight junction protein expression.

CAV1 alleviated CaOx stones formation via suppressing autophagy-dependent ferroptosis.

BackgroundCalcium oxalate (CaOx) is the most common type of kidney stone, but the mechanism of CaOx stones formation remains unclear. The injury of renal cells such as ferroptosis and autophagy has been considered a basis for stones formation.MethodsWe conducted transmission electron microscope (TEM), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and C11-BODIPY analysis to explore whether CaOx could induce autophagy-dependent ferroptosis in vivo and in vitro. To explore the possible mechanism, we conducted bioinformatic analysis of patients with or without CaOx stones, Western blot and qPCR were used to identify the different genes we found in bioinformatic analysis.ResultsIn our study, we found that CaOx could induce autophagy-dependent ferroptosis no matter in vivo or in vitro, which might finally lead to urolithiasis. Bioinformatic analysis of the GSE73680 dataset indicated that the expression of caveolin-1 (CAV1) was higher in control patients than CaOx stone patients, the STRING database indicated that CAV1 might interact with low density lipoprotein receptro-related protein 6 (LRP6), Gene Set Enrichment Analysis (GSEA) showed that the WNT pathway positively associated with the control group while negatively related to the stone group, and LRP6 was the core gene of the WNT pathway. Western blot found that CAV1, LRP6, and Wnt/β-Catenin were decreased in Human Kidney2 (HK2) cells stimulated with CaOx. Furthermore, the WNT pathway was considered to be involved in autophagy and ferroptosis.ConclusionsWe presumed that CAV1 could ameliorate autophagy-dependent ferroptosis through the LRP6/Wnt/β-Catenin axis, and finally alleviate CaOx stone formation.

Caveolin-1 and Its Functional Peptide CSP7 Affect Silica-Induced Pulmonary Fibrosis by Regulating Fibroblast Glutaminolysis.

Exposure to silica is a cause of pulmonary fibrosis disease termed silicosis, which leads to respiratory failure and ultimately death. However, what drives fibrosis is not fully elucidated and therapeutic options remain limited. Our previous RNA-sequencing analysis showed that the expression of caveolin-1 (CAV1) was downregulated in silica-inhaled mouse lung tissues. Here, we not only verified that CAV1 was decreased in silica-induced fibrotic mouse lung tissues in both messenger RNA and protein levels, but also found that CSP7, a functional peptide of CAV1, could attenuate pulmonary fibrosis in vivo. Further in vitro experiments revealed that CAV1 reduced the expression of Yes-associated protein 1(YAP1) and affected its nuclear translocation in fibroblasts. In addition, Glutaminase 1 (GLS1), a key regulator of glutaminolysis, was identified to be a downstream effector of YAP1. CAV1 could suppress the activity of YAP1 to decrease the transcription of GLS1, thereby inhibiting fibroblast activation. Taken together, our results demonstrated that CAV1 and its functional peptide CSP7 may be potential molecules or drugs for the prevention and intervention of silicosis.

Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases.

Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.

216.7: The Immunohistochemical Expression of Endothelial Activation Biomarkers Is a Potential Tool to Predict Kidney Allograft Outcomes

Background and Objective: Few reports assessed biomarkers of endothelial activation in kidney allograft biopsies using immunohistochemistry (IHC). This study aimed to analyze the IHC expression of Caveolin-1 (Cav), Von Willebrand Factor (Vwf), and T-Cadherin (Cad) in for-cause allograft biopsies diagnosed as Interstitial Fibrosis and Tubular Atrophy (IF/TA) of unknown etiology and evaluate its association with graft loss. Methods: This was a retrospective single-center cohort study including kidney biopsies performed in a single center between January 2013 and December 2017, whose histological, laboratory and clinical analysis concluded for IF/TA of unknown etiology. Samples with antibody-mediated changes were excluded. Patients were followed for three years after the biopsy or until graft loss/death. Results: Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Cav and Cad were not associated with graft loss. Vwf had good accuracy to predict graft failure (AUC 0.637, 95%CI 0.486-0.788, p = 0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf > 10%) was associated with reduced death-censored graft survival (58.2% versus 85.4%, p = 0.006). The multivariate analysis showed that Vwf > 10% was an independent risk factor for graft loss (HR = 2.88, 95%CI 1.03-8.02, p = 0.043). Conclusion: Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with IF/TA of unknown etiology, probably reflecting immune endothelial activation.

Treadmill exercise decreases cerebral edema in rats with local cerebral infarction by modulating AQP4 polar expression through the caveolin-1/TRPV4 signaling pathway

Rehabilitation therapy is beneficial for patients with ischemic stroke. Our previous study showed that treadmill training is conducive to neurological function in rats that underwent middle cerebral artery occlusion (MCAO). However, whether exercise benefits cerebral edema and the underlying mechanism remain unclear. This study investigated the influence of treadmill exercise on brain edema and the mechanism of its formation and elimination. The MCAO model was established with Sprague-Dawley (SD) rats, and lentivirus-mediated caveolin-1 shRNA was used to investigate the role of caveolin-1 in brain edema. As expected, we found that treadmill exercise has a beneficial effect on brain edema after stroke. Training led to a significant increase in the expression of caveolin-1 and TRPV4; and reduced brain water content and blood-brain barrier (BBB) damage. This treatment also changed the localization of aquaporin-4 (AQP4). Moreover, the effect of treadmill training on the polar expression of AQP4 differed over time. The results showed that early treadmill training inhibited the polar expression of AQP4, and later promoted its expression. However, the rats that were injected with the caveolin-1 shRNA lentivirus exhibited enhanced edema. Caveolin-1 shRNA eliminated the protective effect induced by exercise, which is consistent with the downregulation of TRPV4 expression. The findings indicate that treadmill training improves brain edema through the caveolin-1/TRPV4/AQP4 pathway.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics.

TRAF4 Maintains Deubiquitination of Caveolin-1 to Drive Glioblastoma Stemness and Temozolomide Resistance.

The identification of a TRAF4/Caveolin-1 axis that plays a crucial role in malignant progression of glioblastoma provides new insights into the function of TRAF4 in ubiquitin signaling and suggests TRAF4 as a potential therapeutic target.

Hyperglycemia Aggravates Blood-Brain Barrier Disruption Following Diffuse Axonal Injury by Increasing the Levels of Inflammatory Mediators through the PPARγ/Caveolin-1/TLR4 Pathway.

Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which significantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing inflammation through the PPARγ/caveolin-1/TLR4 pathway.

Targeted Genome Sequencing Identifies Multiple Rare Variants inCaveolin-1 Associated with Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epidemiologic evidence supporting the importance of genetic factors influencing OSA but limited data implicating specific genes. Objectives: To search for rare variants contributing to OSA severity. Methods: Leveraging high-depth genomic sequencing data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the CFS (Cleveland Family Study), followed by multistage gene-based association analyses in independent cohorts for apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry. Measurements and Main Results: Linkage analysis in the CFS identified a suggestive linkage peak on chromosome 7q31 (LOD = 2.31). Gene-based analysis identified 21 noncoding rare variants in CAV1 (Caveolin-1) associated with lower AHI after accounting for multiple comparisons (P = 7.4 × 10-8). These noncoding variants together significantly contributed to the linkage evidence (P < 10-3). Follow-up analysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (P = 0.024) and higher minimum overnight oxygen saturation (P = 0.007). Conclusions: Rare variants in CAV1, a membrane-scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

Caveolin-1 Alleviates Acetaminophen-Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis.

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.