Aims: Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway. PMCA4 activity is inhibited by the small molecule aurintricarboxylic acid (ATA). We hypothesize that inhibition of PMCA4 with ATA might enhance VEGF-induced angiogenesis. Methods and results: We show that inhibition of PMCA4 with ATA in endothelial cells triggers a marked increase in VEGF-activated calcineurin/NFAT signalling that translates into a strong increase in endothelial cell motility and blood vessel formation. ATA enhances VEGF-induced calcineurin signalling by disrupting the interaction between PMCA4 and calcineurin at the endothelial-cell membrane. ATA concentrations at the nanomolar range, that efficiently inhibit PMCA4, had no deleterious effect on endothelial-cell viability or zebrafish embryonic development. However, high ATA concentrations at the micromolar level impaired endothelial cell viability and tubular morphogenesis, and were associated with toxicity in zebrafish embryos. In mice undergoing experimentally-induced hindlimb ischaemia, ATA treatment significantly increased the reperfusion of post-ischaemic limbs. Conclusions: Our study provides evidence for the therapeutic potential of targeting PMCA4 to improve VEGFbased pro-angiogenic interventions. This goal will require the development of refined, highly selective versions of ATA, or the identification of novel PMCA4 inhibitors.
Purpose To investigate differences in plasma clot properties in patients with AF and CAD and compare the effect of warfarin and antiplatelets on clot structure in AF population. Methods We studied 270 patients and divided them into 3 groups: AF on warfarin (n=184), AF on antiplatelets (n=46) and CAD (n=40). Plasma samples were obtained from participants and centrifuged to prepare platelet poor plasma. Assays were performed in 96-well polystyrene microtiter plates. Reagents were diluted in standard buffer (10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid [HEPES], pH 7.4, 150 mM NaCl). Patient plasma samples (25 %) were incubated with tissue plasminogen activator (500 ng.mL-1) for 10 minutes at 37 Ê C before the addition of CaCl2 (7.5 mM).Either PPP reagent (2.5 %), aPPT reagent (2.5 %), or thrombin (0.5 U.mL-1) were then added to initiate coagulation. Polymerisation of fibrin in plasma was monitored (DOD340 nm) using a Synergy H1 hybrid multi-mode plate reader, readings were taken in 12 second intervals for up to 60 minutes. Results Comparisons between the 3 groups was performed using Kruskal-Wallis test, with Dunn's post-hoc analysis and Holm-Sidak adjustment. There were no significant differences in clot structure between 3 subgroups. The maximum rate of clot formation was significantly delayed in the warfarin subgroup with all reagents used (p<0.001) (table 1). Plasma clot susceptibility to fibrinolysis increased with warfarin compared to antiplatelets but was significant only with APPT and thrombin reagents (p<0.001 and 0.04 respectively). Conclusion Warfarin was effective in delaying clot formation compared to antiplatelets and also resulted in increased susceptibility of plasma clot to fibrinolysis. Conflict of interest None BS43ABSTRACT WITHDRAWN
Conclusion The data show that higher levels of IgM antibodies, including IgM anti-MDA, are associated with a decreased coronary necrotic core volume and lipid core burden, whereas total serum IgG and IgG anti-MDA LDL antibodies were not related to the measured plaque characteristics. The ability of IgM antibodies but not HDL-or LDL-cholesterol levels to indicate these important plaque characteristics is consistent with a proposed mechanistic role. Pulmonary arterial hypertension (PAH) is a chronic and lifethreatening disease with high morbidity and mortality in adult and paediatric patients. PAH is characterised by a progressive narrowing and occlusion of small pulmonary arteries leading to increased pulmonary resistance, right ventricular hypertrophy, and, finally, right ventricular failure. 156A large body of data has shown that proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) represent key events in the vascular remodelling of pulmonary arteries that occurs during PAH. Levels of cytoplasmic calcium are an important determinant of PASMC proliferation and migration, and failure in maintaining appropriate levels of intracellular calcium are associated with PAH. The plasma membrane calcium ATPase (PMCA) proteins extrude calcium from the cytosol to the extracellular medium, and in doing so, play a critical role in the modulation of intracellular calcium levels. In this work, we have investigated whether inducers of PAH trigger any changes in the expression of PMCA proteins in PASMCs.Analysis of RNA expression levels for PMCA genes has revealed that treatment of PASMCs with PDGF results in a significant increase in the level of the RNA encoding for the protein PMCA1. Interestingly, PMCA1 RNA levels were also elevated in lungs of rats with monocrotaline-induced PAH. No changes were observed in the RNA levels for PMCA4, the other major PMCA isoform expressed in PASMCs. Although previous studies on the regulation of PMCA1 gene expression have identified functional binding sites for the transcription factors NFAT in the PMCA1 promoter region, we show here that PDGF-mediated upregulation of PMCA1 transcriptional expression is independent of activation of the calcineurin/ NFAT signalling pathway.Our results suggest the involvement of PMCA1 in PASMC deregulation during PAH, although determination of the link between increased expression of PMCA1 and PAH requires further investigation. Introduction Genome wide association studies have identified Tribbles-1 (TRIB1) to be significantly associated with all major plasma lipid traits and as a risk factor for ischaemic heart disease and myocardial infarction. Studies in mice using Trib1 full body KO and liver-specific over-expression and KO models have shown that hepatic expression of TRIB1 reduces circulating lipids. Additionally, Trib1 has been implicated as a regulator of alternatively activated macrophages. However the potential interplay between hepatocytes, macrophages and Trib1 remain unexplored. MYELOID EXPRESSION OF TRIB1 REGULATES THE POLA...
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