Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.

ConclusionWe successfully upscaled hiPSC-CM derived EHT to a clinically relevant size and were able to demonstrate feasibility and integration using a rabbit model of myocardial infarction. Tissue engineering strategies may be the preferred modality of cell delivery for future cardiac regenerative medicine studies.

range of vascular pathologies including vascular inflammation and atherosclerosis. While TNF-a has shown to regulate Tie receptors, the chronic impact IL-1b has on Ang-1/Tie receptor signalling pathway and vascular function has not been investigated. Aim To examine the impact IL-1b has on Tie receptor expression and Angiopoietin-1 induced PI3Kinase/AKT activity in endothelial cells. Method Primary Human Umbilical Vein Endothelial Cells (HUVEC) were stimulated with 25ng/ml of IL-1b in the presence or absence of 100ng/ml of human recombinant Ang-1. The treatment times ranged from 0 to 48h. Cell lysates from the treated cells were then subjected to Western blotting to analyze Tie receptor levels and phospho-AKT (pAKT), a signaling molecule associated with Ang-1 cellular transduction. The levels of target proteins were compared between reactions by quantifying mean intensity of bands.In addition, cells were treated with Ang-1 in the absence or presence of IL-1b at various time points. The cell viability assay was performed on the treated cells by following the manufactures protocol. The mean percentage of live to dead cells was calculated from three random fields for each treatment.Data for the Tie receptor and AKT analysis is presented as means and SEM of three independent experiments. Statistical significance represented with p<0.05 using Student's t-test. Data for the cell viability assay is presented as means and SEM of two independent experiments. Results A significant reduction in the levels of Tie-1 receptor was observed at 3h (58.6±8.6%) in HUVECs treated with IL-1b. The cytokine was able to maintain significant low levels of Tie1 up until 48h of treatment, whereas the changes in levels of Tie-2 were insignificant. Interestingly, IL-1b significantly reduced Ang1-induced pAKT activity from 3h onwards with maximum reduction of 73.4±12.8% observed at 48h. The cell viability assays showed reduction in the percentage live to dead cells between Ang-1 and Ang1 + IL-1b for chronic time points tested. Conclusion Long term exposure of Interleukin-1b is capable of altering Tie-1 levels and increasing the Tie-2: Tie-1 ratio in endothelial cells. In contracts, IL-1b reduces Ang-1-PI3Kinase/ AKT signalling and endothelium cell viability. This opposing phenomenon observed where IL-1b impairs Ang-1 protective ability suggests and different mechanism of regulation, independent of the Tie-1 receptor.

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