Vascular endothelial growth factor (VEGF), a potent angiogenic and cell-specific mitogen, is up-regulated by hypoxia. However, the mechanism(s) responsible for hypoxic induction of VEGF has not been clearly delineated. We report that steady state mRNA levels are increased 12 +/- 0.6-fold, but transcriptional rate only 3.1 0.6-fold hypoxia in PC12 cells. In order to investigate cis-regulatory sequences which mediate this response hypoxia, we cloned rat genomic encoding identified 28-base pair...

Inactivation of the von Hippel-Lindau protein (pVHL) has been implicated in pathogenesis renal carcinomas and central nervous system hemangioblastomas. These are highly vascular tumors which overproduce angiogenic peptides such as endothelial growth factor/vascular permeability factor (VEGF/VPF). Renal carcinoma cells lacking wild-type pVHL were found to produce mRNAs encoding VEGF/VPF, glucose transporter GLUT1, platelet-derived B chain under both normoxic hypoxic conditions. Reintroduction...

The major control point for the hypoxic induction of vascular endothelial growth factor (VEGF) gene is regulation steady-state level mRNA. We previously demonstrated a discrepancy between transcription rate and mRNA induced by hypoxia. This led us to examine post-transcriptional VEGF expression. Actinomycin D experiments revealed that hypoxia increased half-life from 43 ± 6 min 106 9 min. Using an in vitro degradation assay, 3′-untranslated region (UTR) transcripts were also found be when...

Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit subgroups with increased oxidative stress. Haptoglobin (Hp), major antioxidant protein, is determinant events patients Type 2 diabetes mellitus (DM). The Hp gene polymorphic common alleles, 1 and 2. allelic protein product provides inferior protection compared the product. We sought test hypothesis that could reduce DM individuals 2-2 genotype,...

A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance the can be mediated by monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for Hp 2 allele (Hp 2-2) were at 500% greater risk cardiovascular disease (CVD) compared with 1 1-1). No differences in type seen without diabetes. To understand relationship between polymorphism CVD, we...

Background —The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability the degree of new formation patients with disease. The basis for this heterogeneity not understood. In study we test hypothesis that failure to generate vessels associated appropriately induce hypoxia or angiogenic factor, vascular endothelial growth factor (VEGF). Methods Results —We correlated VEGF...

Collateral blood vessels supplement normal coronary flow and compromised by artery disease, thereby protecting the myocardium from ischemia. vessel formation is result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability (VPF), a secreted mitogen specific for cells an extremely potent angiogenic factor. In present study, VPF/VEGF mRNA protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes vitro response reduction oxygen...

Hypoxia induces an increase in the stability of mRNA encoding vascular endothelial growth factor (VEGF). We have previously demonstrated that a 500-base region 3'-untranslated VEGF is critical for stabilization vitro degradation assay forms RNA-protein complex hypoxia-inducible fashion. report here identification three adenylate-uridylate-rich RNA elements within this form identical or closely related complex. This constitutively elevated tumor cell line lacking wild type von Hippel-Lindau...

We have recently demonstrated in multiple independent population-based longitudinal and cross sectional analyses that the haptoglobin 2-2 genotype is associated with an increased risk for diabetic cardiovascular disease. The chief function of (Hp) to bind hemoglobin thereby prevent hemoglobin-induced oxidative tissue damage. This antioxidant mediated part by ability release iron from on its binding. hypothesized there may be diabetes- genotype-dependent differences amount catalytically...

Association of paraoxonase 1 (PON1) with high-density lipoprotein (HDL) stabilizes the enzyme. In diabetic patients, PON1 dissociates from HDL and, as a consequence, is less biologically active. Our aim was to investigate effects Wonderful variety pomegranate juice (WPJ) and polyphenol extract (WPOMxl) consumption on association in patients. Thirty patients type 2 diabetes mellitus participated study. Ten male 10 female received concentrated WPJ (50 mL/day for 4 weeks), while another group...

Stability of the vascular endothelial growth factor (VEGF) mRNA is tightly regulated through its 3′-untranslated region (3′-UTR). Here, we demonstrate that VEGF levels are increased by anisomycin, a strong activator stress-activated protein kinases. Hence, induction inhibited SB202190, an inhibitor JNK and p38/HOG kinase. Furthermore, expression in cells overexpress increase stability. We show two different approaches anisomycin exerts effect on 3′-UTR. First, using vitro degradation assay,...

Cytokine stimulation of human DLD-1 cells resulted in a marked expression nitric-oxide synthase (NOS) II mRNA and protein accompanied by only moderate increase transcriptional activity. Also, there was basal transcription the NOS gene, which did not result measurable expression. The 3′-untranslated region (3′-UTR) contains four AUUUA motifs one AUUUUA motif, known to destabilize mRNAs proto-oncogenes, nuclear factors, cytokines. Luciferase reporter gene constructs containing 3′-UTR showed...

Insulin-like growth factor I (IGF-I) and vascular endothelial (VEGF) levels are correlated with retinal ischemia-associated intraocular neovascu-larization in humans. Since VEGF is required for iris neovascularization animal models of ischemia, we tested whether IGF-I could act as an indirect angiogenic by increasing gene expression. increased pigment epithelial (RPE) cell mRNA a concentration-dependent manner EC50 7 nmol/l (53.6 ng/ml). RPE bovine smooth muscle cells exposed to 50 nmol/1...

A genetically defined molecular heterogeneity of haptoglobin, characterized by the major phenotypic forms Hp 1-1, 2-1, and 2-2, has been associated with distinct clinical manifestations. To enable use DNA samples for study this polymorphism, we established a haptoglobin genotyping method based on PCR.Taking advantage selectivity PCR, amplified segments specifically representing alleles 1 2 from genomic DNA. The products were analyzed agarose gel electrophoresis. Haptoglobin phenotyping...

Intraplaque hemorrhage increases the risk of plaque rupture and thrombosis. The release hemoglobin (Hb) from extravasated erythrocytes at site leads to iron deposition, which may increase oxidation inflammation in atherosclerotic plaque. haptoglobin (Hp) protein is critical for protection against Hb-induced injury. Two common alleles exist Hp locus 2 allele has been associated with increased myocardial infarction. We have demonstrated decreased anti-oxidative anti-inflammatory activity...

Patients with diabetes presenting acute myocardial infarction (AMI) have an increased rate of death and heart failure. homozygous for the haptoglobin (Hp) 1 allele (Hp 1-1) develop fewer vascular complications. We tested hypothesis that Hp type is related to outcome patients AMI. prospectively assessed relationship between 30-day mortality failure in 1,437 AMI (506 diabetes). Multivariate logistic regression identified a significant interaction status on these measures. was not among without...

In individuals with diabetes mellitus (DM), the haptoglobin (Hp) genotype is a major determinant of susceptibility to myocardial infarction. We have proposed that this because DM and Hp genotype–dependent differences in response intraplaque hemorrhage. The macrophage hemoglobin scavenging receptor CD163 plays an essential role clearance released from lysed red blood cells after sought test hypothesis expression genotype–dependent. was quantified plaques by immunohistochemistry, on peripheral...

Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, prospective placebo-controlled study, recently demonstrated that vitamin could dramatically reduce CVD in individuals diabetes and the haptoglobin (Hp) 2-2 genotype (40% diabetic individuals). However, because large number clinical trials failed to demonstrate benefit from coupled lack mechanistic explanation for why should be beneficial only Hp genotype, enthusiasm...