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Background:  The myeloid enzyme 12/15-lipoxygenase (LOX), which generates bioactive oxidized lipids, has been implicated in numerous inflammatory diseases, with several studies demonstrating an improvement in pathology in mice lacking the enzyme. However, the ability of 12/15-LOX to directly regulate B cell function has not been studied. Methods:  The influence of 12/15-LOX on B cell phenotype and function, and IgM generation, was compared using wildtype (WT) and 12/15-LOX ( Alox15 -/- ) deficient mice. The proliferative and functional capacity of splenic CD19 + B cells was measured in vitro in response to various toll-like receptor agonists. Results:  WT and Alox15 -/- displayed comparable responses. However in vivo , splenic B cell numbers were significantly elevated in Alox15 -/- mice with a corresponding elevation in titres of total IgM in lung, gut and serum, and lower serum IgM directed against the 12/15-LOX product, 12-hydroxyeicosatetraenoic acid-phosphatidylethanolamine (HETE-PE). Discussion:  Myeloid 12/15-LOX can regulate B cell numbers and innate immune antibody levels in vivo , potentially contributing to its ability to regulate inflammatory disease. Furthermore, the alterations seen in 12/15-LOX deficiency likely result from changes in the equilibrium of the immune system that develop from birth. Further studies in disease models are warranted to elucidate the contribution of 12/15-LOX mediated alterations in B cell numbers and innate immune antibody generation to driving inflammation in vivo .

Dietary zinc deficiency affects one third of the world’s population and has more recently been associated with the development of atherosclerosis, however, its role in vascular smooth muscle cell (VSMC) function remains uncharacterised. VSMC’s are necessary for maintaining atherosclerotic plaque stability and any complications in VSMC function could have serious implications in vascular disease. The main aim of this study was to utilise in vivo and in vitro models of zinc deficiency to ascertain the effects this has on VSMC signalling processes. Rats were maintained on 2 and 6 weeks marginally zinc deficient diets which induced lower serum zinc concentrations. Carotid and aortic arterial tissue samples dissected from zinc deficient rats had significantly higher levels of VSMC apoptosis compared to those maintained on a zinc adequate diet. This occurred in parallel with increased dephosphorylation of the Bcl-2 associated death promoter (BAD) and attenuation of the pro-survival ERK1/2 pathway which maintains BAD in an inactive phosphorylated state. Two further mechanisms were further elucidated in vitro. Primary rat aortic smooth muscle cells (PRASMC) were incubated with plasma from zinc deficient rats and resulted in increased apoptosis and an overexpression of BAD similar to in vivo observations. However, this also occurred via sustained increases in [Ca2+]i leading to the activation of the BAD phosphatase calcineurin (which promotes activation of BAD via dephosphorylation) and increased oxidative stress. Further results have demonstrated that plasma from zinc deficient rats inhibits VSMC migration via decreased activity of osteopontin (OPN) an integrin receptor ligand and reduced activation of CREB. In addition, VSMC proliferation and differentiation in zinc deficiency was also assessed but no significant change was detected. Furthermore, these results were not due to a direct effect of zinc deficient environment rather secondary mechanisms in vivo via mediators released into the plasma. Taken together these findings demonstrate that marginally zinc deficient diets can induce VSMC apoptosis and decreased migration which may influence cardiovascular diseases such as atherosclerosis by inducing plaque vulnerability and further vascular complications.

Extracellular vesicles (EVs) carry unique repertoires of biologically active cargo that hold promise as novel biomarkers and future interventional targets for cardiovascular diseases (CVDs). However, it is unclear as to how the number, location, cellular origin, and size of these EVs within the circulation relate to the development of CVDs such as coronary artery disease (CAD). The current study compared these novel markers in arterial and venous blood samples in individuals undergoing coronary assessment with angiography.. EVs were then characterized from those presenting with and without CAD. Arterial and venous blood samples were collected from individuals with confirmed CAD following coronary angiography and a matched cohort in whom there was no evidence of disease. EV fractions were isolated from 500µL of platelet free plasma (PFP) by size exclusion chromatography. EVs were analyzed by Nanoparticle Tracking Analysis and flow cytometry to characterize number, size and cellular origin. A thrombin generation assay was used to assess the pro-coagulatory activity of the isolated circulating EVs. Proteomics was used to determine the protein cargo carried within the EVs. Coagulatory activity of EVs isolated from CAD patients was significantly higher in when compared to controls, although the numbers of EVs did not differ. There were higher numbers of endothelial-derived EVs in arterial blood compared with venous blood. Linear regression models revealed that plasma triacylglycerol concentration and age independently predicted circulating EV numbers in CAD patients. Proteomics revealed several proteins associated with coagulation upregulated in patients with CAD. Although the absolute numbers of EVs in CAD patients were not elevated, EVs in CAD patients had greater pro-coagulant activity, highlighting a potentially important role for EVs in the pathogenesis of CAD. CAD patients displayed a greater EV-induced thrombin generation capability when compated to those with no disease. The proteomic profile of arterial-derived EVs in patients with CAD demonstrated several proteins associated with coagulation that may be a risk factor for developing a future event. The identification of EVs in patients with CAD with upregulated coagulation proteins may be a novel biomarker for the development of future events and may identify a high risk patient group that may benefit for more aggressive cardiovascular risk intervention.