ABSTRACT
Endothelial progenitor cells (EPCs) play an important role in endothelial repair and vascular regeneration. Growth arrest-speciï¬c gene 6 (Gas6) is a novel key regulator of the vascular system, which is linked to a number of cardiovascular diseases. However, the effects of Gas6 on EPCs have not been elucidated to date. The present study was designed to determine the biological function of EPCs treated with Gas6 and to eludicate the underlying mechanisms. EPCs were isolated from umbilical cord blood and treated with various concentrations (25, 50, 100 and 200 ng/ml) of Gas6. The proliferation, migration and angiogenesis of the Gas6-treated EPCs were evaluated by MTT assay, Transwell assay and in vitro tube formation assay, respectively. The phosphorylation status of AKT and ERK was evaluated by western blot analysis. The results demonstrated that treatment with Gas6 enhanced the proliferation and migration of the EPCs in a dose-dependent manner. However, Gas6 did not promote the differentiation of EPCs on Matrigel. Gas6 induced the phosphorylation of AKT, but not that of ERK. The enhanced proliferation and migration induced by Gas6 was markedly suppressed by the inhibitor of PI3K but not by that of ERK. These results suggest that Gas6 activates the AKT signaling pathway, which, in turn, promotes the proliferation and migration of EPCs.
Subject(s)
Endothelial Progenitor Cells/metabolism , Intercellular Signaling Peptides and Proteins/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Endothelial Progenitor Cells/cytology , Endothelial Progenitor Cells/drug effects , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Fetal Blood/cytology , Fetal Blood/metabolism , Gene Expression Regulation , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Neovascularization, Physiologic , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Concerns have arisen regarding the risk of ischemic heart disease with the novel antiangiogenic agent bevacizumab, a recombinant humanised monoclonal antibody to the vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in ischemic heart disease is controversial. This meta-analysis was therefore performed to assess the overall risk of ischemic heart disease associated with the use of bevacizumab. The databases of PubMed, EMBASE and Web of Science were searched for English language studies of randomised controlled trials comparing bevacizumab with control therapy published through October 25, 2012. Summary incidence rates, relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of the included studies. A total of 4,617 patients from 7 randomised controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidence of ischemic heart disease was 1.0% (95% CI, 0.6%-1.4%). Patients treated with bevacizumab had a significantly increased risk of ischemic heart disease with an RR of 2.49 (95% CI, 1.37-4.52) compared with controls. In addition, both high doses and low doses of bevacizumab increased the risk of cardiac ischemia (low dose at 2.5 mg/kg per week: RR, 2.14 [95% CI, 1.09-4.19]; high dose at 5 mg/kg per week: RR, 4.81 [95% CI, 1.03-22.42]). Bevacizumab was also found to significantly increase the risk of cardiac ischemia in patients with colorectal cancer (RR, 2.13; 95% CI, 1.11-4.06) compared with controls. This meta-analysis shows the use of bevacizumab was associated with an increased risk of developing ischemic heart disease in colorectal cancer patients receiving this drug. Our conclusions are limited by the available data. Further evaluations of high-quality RCTs are needed.
