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Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells.

ABSTRACT: The present study investigated the effect of the combretastatin A-4 analogue CPU-XT-008 on the proliferation, apoptosis and expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) in human umbilical vein endothelial cells (HUVECs). The proliferation capacity of HUVECs was analyzed with a cell viability assay, while their apoptosis and migration abilities were evaluated via flow cytometry and monolayer denudation assay, respectively. The mRNA and protein expression levels of VEGF and FGF-2 in these cells were determined by reverse transcription-polymerase chain reaction, and cell-based ELISA, western blotting and immunocytochemistry, respectively. The results demonstrated that CPU-XT-008 inhibited proliferation and migration, and induced apoptosis in HUVECs in a dose-dependent manner. In addition, CPU-XT-008 downregulated the mRNA and protein expression levels of VEGF and FGF-2 in these cells. These findings suggest that CPU-XT-008 exerts anti-angiogenic effects in HUVECs, which may explain the inhibition of cell proliferation and migration, induction of apoptosis, and reduction in the mRNA and protein expression levels of VEGF and FGF-2 observed in the present study.

SUBMITTER: Xiong R

PROVIDER: S-EPMC4727199 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells.

Xiong Rui R Sun Jing J Liu Kun K Xu Yungen Y He Shuying S

Oncology letters 20151105 1

The present study investigated the effect of the combretastatin A-4 analogue CPU-XT-008 on the proliferation, apoptosis and expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) in human umbilical vein endothelial cells (HUVECs). The proliferation capacity of HUVECs was analyzed with a cell viability assay, while their apoptosis and migration abilities were evaluated via flow cytometry and monolayer denudation assay, respectively. The mRNA and protein ...[more]

PMID: 26870239

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Project description:BACKGROUND:Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. RESULTS:Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n?=?11) versus control (n?=?8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. CONCLUSION:This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FGR samples; NRM is involved in cardiac remodeling, and lincRNAs are correlated with cardiovascular diseases. Future studies should elucidate whether the downregulated LGALS1 and FPR3 expressions in FGR are angiogenesis-modulating regulators leading to placental insufficiency-induced FGR or whether the expression of these genes can be used as a biomarker for increased cardiovascular risk. Altered DNA methylation might partly underlie FPR3 and NRM differential gene expression differences in a sex-dependent manner.

Project description:Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of ADMA lead to reduction in nitric oxide (NO) production, which is linked to endothelial dysfunction and atherosclerosis. Piper sarmentosum is an herb that has shown stimulation on endothelial NO production by increasing both expression and activity of eNOS. Thus, this study determined whether the positive effect of P. sarmentosum on NO production is related to its modulation on the DDAH-ADMA pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to tumor necrosis factor-? (TNF-?). HUVEC were divided into four groups: control, treatment with 250 µg/ml of aqueous extract of P. sarmentosum leaves (AEPS), treatment with 30 ng/ml of TNF-?, and concomitant treatment with AEPS and TNF-? for 24 h. After treatments, HUVEC were collected to measure DDAH1 messenger RNA (mRNA) expression using quantitative real-time polymerase chain reaction. DDAH1 protein level was measured using enzyme-linked immunosorbent assay (ELISA), and DDAH enzyme activity was measured using colorimetric assay. ADMA concentration was measured using ELISA, and NO level was measured using Griess assay. Compared to control, TNF-?-treated HUVEC showed reduction in DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05). Treatment with AEPS successfully increased DDAH1 mRNA expression (P < 0.05), DDAH1 protein level (P < 0.01), and DDAH activity (P < 0.05) in TNF-?-treated HUVEC. Treatment with TNF-? caused an increase in ADMA level (P < 0.01) and a decrease in endothelial NO production (P < 0.001). Whereas treatment with AEPS was able to reduce ADMA level (P < 0.01) and restore NO (P < 0.001) in TNF-?-treated HUVEC. The results suggested that AEPS promotes endothelial NO production by stimulating DDAH activity and thus reducing ADMA level in TNF-?-treated HUVEC.

Dataset Information

Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells.

Publications

Effect of CPU-XT-008, a combretastatin A-4 analogue, on the proliferation, apoptosis and expression of vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells.

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