Dataset Information

CXCR7/p-ERK-Signaling Is a Novel Target for Therapeutic Vasculogenesis in Patients with Coronary Artery Disease.

ABSTRACT: Coronary artery disease (CAD) is characterized by insufficient vasculogenic response to ischemia, which is typically accompanied by dysfunction of endothelial outgrowth cells (EOCs). CXC chemokine receptor 7 (CXCR7) is a key modulator of the neovascularization of EOCs to perfusion defect area. However, the mechanism underlying the role of EOCs in CAD-related abnormal vasculogenesis is still not clear. Here, we investigated the alteration of EOCs-related vasculogenic capacity in patients with CAD and its potential mechanism. Compared with EOCs isolated from healthy subjects, EOCs from CAD patients showed an impaired vasculogenic function in vitro. CXCR7 expression of EOCs from CAD patients was downregulated. Meanwhile, the phosphorylation of extracellular signal-regulated kinase (ERK), downstream of CXCR7 signaling, was also reduced. CXCR7 expression introduced by adenovirus increased the phosphorylation of ERK, which was parallel to improved function of EOCs. The enhanced adhesion and vasculogenesis of EOCs can be blocked by short interfering RNA (siRNA) against CXCR7 and ERK inhibitor PD098059. Therefore, our study demonstrates that the upregulation of CXCR7 signaling contributes to increased vasculogenic capacity of EOCs from CAD patients, indicating that CXCR7 signaling may be a novel therapeutic vasculogenic target for CAD.

SUBMITTER: Cao Z

PROVIDER: S-EPMC5017667 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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CXCR7/p-ERK-Signaling Is a Novel Target for Therapeutic Vasculogenesis in Patients with Coronary Artery Disease.

Cao Zheng Z Tong Xinzhu X Xia Wenhao W Chen Long L Zhang Xiaoyu X Yu Bingbo B Yang Zhen Z Tao Jun J

PloS one 20160909 9

Coronary artery disease (CAD) is characterized by insufficient vasculogenic response to ischemia, which is typically accompanied by dysfunction of endothelial outgrowth cells (EOCs). CXC chemokine receptor 7 (CXCR7) is a key modulator of the neovascularization of EOCs to perfusion defect area. However, the mechanism underlying the role of EOCs in CAD-related abnormal vasculogenesis is still not clear. Here, we investigated the alteration of EOCs-related vasculogenic capacity in patients with CAD ...[more]

PMID: 27612090

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Project description:BackgroundDysfunction in the late Endothelial Progenitor Cells (EPCs) is responsible for endothelial repair in patients with Coronary Artery Disease (CAD), and the shear stress is beneficial for EPCs function. However, the impact of shear stress on the capacity of EPCs in CAD patients has not been elucidated yet. The C-X-C chemokine receptor 7/extracellular signal-regulated kinase (CXCR7)/(ERK) pathways are identified to regulate EPCs function in CAD patients. Here, we hypothesize that shear stress upregulates the CXCR7/ERK pathways, which restore the EPCs function in CAD patients.MethodsThe human Peripheral Blood Mononuclear Cells (PBMCs) were collected from healthy adults and CAD patients and then used for EPCs cultivation. The Lv-siRNA for human CXCR7 was transfected into induced EPCs isolated from the CAD patients. Meanwhile, the EPCs from CAD patients were subjected to shear stress generated by a biomimetic device. Next, the cell viability, migration, tube formation, and apoptosis were detected by CCK-8, Transwell assay, Matrigel, and flow cytometry, respectively. Also, the CXCR7/ERK pathways in human EPCs were analyzed by Western blotting and qRT-PCR.ResultCompared to the EPCs collected from normal adults, the CAD patient-derived EPCs showed reduced in vitro vasculogenic capacity. Also, the level of CXCR7 in CAD patient-derived EPCs was significantly reduced compared to the EPCs of healthy subjects. Meanwhile, the extracellular signal-regulated kinase (ERK), which represents a CXCR7 downstream signaling pathway, had decreased phosphorylation level. The shear stress treatment augmented the CXCR7 expression and also elevated ERK phosphorylation, which is comparable to the up-regulation of CAD patient-derived EPCs function. Further, the small interfering RNA (siRNA)-mediated CXCR7 knockdown diminished the enhanced migration, adhesion, and tube formation capacity of shear stress treated CAD patient-derived EPCs.ConclusionUp-regulation of the CXCR7/ERK pathways by shear stress can be a promising new target in enhancing the vasculogenic ability of CAD patient-derived EPCs.

Project description:BackgroundMetastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC.MethodsTo identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers.ResultsTranscriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.ConclusionsWe conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

Project description:BackgroundCoronary artery disease (CAD) is a complex illness with unknown pathophysiology. Peripheral biomarkers are a non-invasive method required to track the onset and progression of CAD and have unbeatable benefits in terms of early identification, prognostic assessment, and categorization of the diagnosis. This study aimed to identify and validate the diagnostic and therapeutic potential of differentially expressed immune-related genes (DE-IRGs) in CAD, which will aid in improving our knowledge on the etiology of CAD and in forming genetic predictions.MethodsFirst, we searched coronary heart disease in the Gene Expression Omnibus (GEO) database and identified GSE20680 (CAD = 87, Normal = 52) as the trial set and GSE20681 (CAD = 99, Normal = 99) as the validation set. Functional enrichment analysis using protein-protein interactions (PPIs), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out on the identified differentially expressed genes. Optimal feature genes (OFGs) were generated using the support vector machine recursive feature elimination algorithm and the least absolute shrinkage and selection operator (LASSO) algorithm. Furthermore, immune infiltration in CAD patients and healthy controls was compared using CIBERSORT, and the relationship between immune cells and OFGs was examined. In addition, we constructed potential targeted drugs for this model through the Drug-Gene Interaction database (DGIdb) database. Finally, we verify the expression of S100A8-dominated OFGs in the GSE20681 dataset to confirm the universality of our study.ResultsWe identified the ten best OFGs for CAD from the DE-IRGs. Functional enrichment analysis showed that these marker genes are crucial for receptor-ligand activity, signaling receptor activator activity, and positive control of the response to stimuli from the outside world. Additionally, CIBERSORT revealed that S100A8 could be connected to alterations in the immune microenvironment in CAD patients. Furthermore, with the help of DGIdb and Cytoscape, a total of 64 medicines that target five marker genes were subsequently discovered. Finally, we verified the expression of the OFGs genes in the GSE20681 dataset between CAD patients and normal patients and found that there was also a significant difference in the expression of S100A8.ConclusionWe created a 10-gene immune-related prognostic model for CAD and confirmed its validity. The model can identify potential biomarkers for CAD prediction and more accurately gauge the progression of the disease.

Dataset Information

CXCR7/p-ERK-Signaling Is a Novel Target for Therapeutic Vasculogenesis in Patients with Coronary Artery Disease.

Publications

CXCR7/p-ERK-Signaling Is a Novel Target for Therapeutic Vasculogenesis in Patients with Coronary Artery Disease.

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