Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against β-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI).

A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion.

Aims: Endothelial erosion of plaques is responsible for ∼30% of acute coronary syndromes (ACS). Smoking is a risk factor for plaque erosion, which most frequently occurs on the upstream surface of plaques where the endothelium experiences elevated shear stress. We sought to recreate these conditions in vitro to identify potential pathological mechanisms that might be of relevance to plaque erosion.

Internal Mammary Arteries as a Model to Demonstrate Restoration of the Impaired Vasodilation in Hypertension, Using Liposomal Delivery of the CYP1B1 Inhibitor, 2,3',4,5'-Tetramethoxystilbene.

A significant number of patients with severe cardiovascular disease, undergoing coronary artery bypass grafting (CABG), present with hypertension. While internal mammary arteries (IMAs) may be a better alternative to vein grafts, their impaired vasodilator function affects their patency. Our objectives were to (1) determine if inhibition of the cytochrome P450 enzyme CYP1B1, using liposome-encapsulated 2,3′,4,5′-tetramethoxystilbene (TMS), can potentiate vasodilation of IMAs from CABG patients, and (2) assess mechanisms involved using coronary arteries from normal rats, in an ex vivo model of hypertension.

Nanostructured Lipid Carriers Deliver Resveratrol, Restoring Attenuated Dilation in Small Coronary Arteries, via the AMPK Pathway.

Nanostructured lipid carriers (NLCs) are an emerging drug delivery platform for improved drug stability and the bioavailability of antihypertensive drugs and vasoprotective nutraceutical compounds, such as resveratrol (RV). The objective of this study was to ascertain NLCs' potential to deliver RV and restore attenuated dilator function, using an ex vivo model of acute hypertension. Trimyristin-triolein NLCs were synthesized and loaded with RV.

The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies.

The conceptual technology of small molecule glycomimetics, exemplified by compounds , has shown promising protective effects against lipid-induced endothelial dysfunction, restorative effects on diabetic endothelial colony forming cells, and preventative effects on downstream vascular calcification amongst other important and studies. We report the optimised synthesis of an array of 17 small molecule glycomimetics, including the regio-, enantio- and diastereo-meric sulfated scaffolds of a hit structure along with novel desulfated examples. For the first time, the absolute stereochemical configurations of have been clarified based on an identified and consistent anomaly with the Sharpless asymmetric dihydroxylation reaction.

Loss of SIRT1 in diabetes accelerates DNA damage-induced vascular calcification.

Aims: Vascular calcification is a recognized predictor of cardiovascular risk in the diabetic patient, with DNA damage and accelerated senescence linked to oxidative stress-associated pathological calcification. Having previously shown that systemic SIRT1 is reduced in diabetes, the aim was to establish whether SIRT1 is protective against a DNA damage-induced senescent and calcified phenotype in diabetic vascular smooth muscle cells (vSMCs).

Methods And Results: Immunohistochemistry revealed decreased SIRT1 and increased DNA damage marker expression in diabetic calcified arteries compared to non-diabetic and non-calcified controls, strengthened by findings that vSMCs isolated from diabetic patients show elevated DNA damage and senescence, assessed by the Comet assay and telomere length.

Tetramethoxystilbene-Loaded Liposomes Restore Reactive-Oxygen-Species-Mediated Attenuation of Dilator Responses in Rat Aortic Vessels Ex vivo.

The methylated analogue of the polyphenol resveratrol (RV), 2,3',4,5'-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues.

Salt and Water Retention Is Associated with Microinflammation and Endothelial Injury in Chronic Kidney Disease.

Background: Progressive chronic kidney disease (CKD) inevitably leads to salt and water retention and disturbances in the macro-and microcirculation.

Objectives: We hypothesize that salt and water dysregulation in advanced CKD may be linked to inflammation and microvascular injury pathways.

Methods: We studied 23 CKD stage 5 patients and 11 healthy controls (HC).

Small Molecule Glycomimetics Inhibit Vascular Calcification via c-Met/Notch3/HES1 Signalling.

Background/aims: Vascular calcification represents a huge clinical problem contributing to adverse cardiovascular events, with no effective treatment currently available. Upregulation of hepatocyte growth factor has been linked with vascular calcification, and thus, represent a potential target in the development of a novel therapeutic strategy. Glycomimetics have been shown to interrupt HGF-receptor signalling, therefore this study investigated the effect of novel glycomimetics on osteogenic signalling and vascular calcification in vitro.

Diabetic endothelial colony forming cells have the potential for restoration with glycomimetics.

Endothelial colony forming progenitor cell (ECFC) function is compromised in diabetes, leading to poor vascular endothelial repair, which contributes to impaired diabetic foot ulcer healing. We have generated novel glycomimetic drugs with protective effects against endothelial dysfunction. We investigated the effect of glycomimetic C3 on the functional capacity of diabetic ECFCs.

Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE-related factors.

Objectives: We aimed to describe the rate and determinants of carotid plaque progression and the onset of clinical cardiovascular disease (CVD) in a UK SLE cohort.

Methods: Female patients with SLE of white British ancestry were recruited from clinics in the North-West of England and had a baseline clinical and CVD risk assessment including measurement of carotid intima-media thickness (CIMT) and plaque using B-mode Doppler ultrasound. Patients were followed up (>3.

QRISK3 improves detection of cardiovascular disease risk in patients with systemic lupus erythematosus.

Objective: 10-year cardiovascular disease (CVD) risk scores are calculated using algorithms, including Framingham (worldwide) and QRISK2 (UK). Recently, an updated QRISK3 model was introduced, which considers new variables including SLE and steroid prescription, not included in QRISK2 and Framingham algorithms. We sought to determine the extent to which QRISK3 improves identification of high-risk patients with SLE and whether the score relates to standard and novel markers of SLE-specific endothelial dysfunction.

Endothelial Progenitor Cells: New Targets for Therapeutics for Inflammatory Conditions With High Cardiovascular Risk.

Over the past decade, we have witnessed an exponential growth of interest into the role of endothelial progenitor cells (EPCs) in cardiovascular disease. While the major thinking revolves around EPC angiogenic repair properties, we have used a hypothesis-driven approach to discover disease-related defects in their characteristics and based on these findings, have identified opportunities for functional enhancement, which offer an exciting avenue for translation into clinical intervention. In this review, we focus on two groups; circulating myeloid angiogenic cells (MACs) and late outgrowth endothelial colony forming cells (ECFCs), and will discuss the unique properties and defects of each population, as new insights have been gained into the potential function of each sub-type using current techniques and multiomic technology.

Links between a biomarker profile, cold ischaemic time and clinical outcome following simultaneous pancreas and kidney transplantation.

In sepsis, trauma and major surgery, where an explicit physiological insult leads to a significant systemic inflammatory response, the acute evolution of biomarkers have been delineated. In these settings, Interleukin (IL) -6 and TNF-α are often the first pro-inflammatory markers to rise, stimulating production of acute phase proteins followed by peaks in anti-inflammatory markers. Patients undergoing SPKT as a result of diabetic complications already have an inflammatory phenotype as a result of uraemia and glycaemia.

The Role of Nrf2 in Cardiovascular Function and Disease.

Free radicals, reactive oxygen/nitrogen species (ROS/RNS), hydrogen sulphide, and hydrogen peroxide play an important role in both intracellular and intercellular signaling; however, their production and quenching need to be closely regulated to prevent cellular damage. An imbalance, due to exogenous sources of free radicals and chronic upregulation of endogenous production, contributes to many pathological conditions including cardiovascular disease and also more general processes involved in aging. Nuclear factor erythroid 2-like 2 (NFE2L2; commonly known as Nrf2) is a transcription factor that plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes, through binding to and activating expression of promoters containing the antioxidant response element (ARE).

Endothelial microparticles prevent lipid-induced endothelial damage Akt/eNOS signaling and reduced oxidative stress.

Endothelial microparticles (EMPs) are endothelium-derived submicron vesicles that are released in response to diverse stimuli and are elevated in cardiovascular disease, which is correlated with risk factors. This study investigates the effect of EMPs on endothelial cell function and dysfunction in a model of free fatty acid (FFA) palmitate-induced oxidative stress. EMPs were generated from TNF-α-stimulated HUVECs and quantified by using flow cytometry.

The Association of Baseline and Longitudinal Change in Endothelial Microparticle Count with Mortality in Chronic Kidney Disease.

Background: Chronic kidney disease (CKD) is associated with a unique milieu of vascular pathology, and effective biomarkers of active vascular damage are lacking. A candidate biomarker is the quantification of circulating endothelial microparticles (EMPs). This study observed baseline and longitudinal EMP change (δEMP) and established the association of these with all-cause mortality and cardiovascular events in CKD.

A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling.

Background: Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress.

Vitamin D improves endothelial dysfunction and restores myeloid angiogenic cell function via reduced CXCL-10 expression in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have accelerated cardiovascular disease and dysfunctional endothelial repair mechanisms. Myeloid angiogenic cells (MACs), derived from circulating monocytes, augment vascular repair by paracrine secretion of pro-angiogenic factors. We observed that SLE MACs are dysfunctional and secrete pro-inflammatory cytokines.

Elevated levels of endothelial-derived microparticles, and serum CXCL9 and SCGF-β are associated with unstable asymptomatic carotid plaques.

Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques, and may correlate with serum markers of plaque instability and inflammation. Circulating EMPs, platelet MPs (PMPs) and inflammatory markers were measured in healthy controls and patients undergoing carotid endarterectomy.