The relationship between oxidised LDL, endothelial progenitor cells and coronary endothelial function in patients with CHD.

Objective: The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD).

Methods: 33 patients with stable CHD were studied.

Adventitial ablation technique that permits the assessment of adventitial-dependent contribution to microvascular contractile function.

Resistance arteries have been implicated as a major contributing factor in the sequela of disease conditions such as hypertension and diabetes and, as such, are a major focus of cardiovascular research. The paracrine influence of the intimal endothelial layer of resistance arteries is well established. Considering the growing body of evidence substantiating a functionally relevant vascular adventitia, in this study we have established a technique that permits determination of the functional influence of the adventitial layer on resistance artery tone.

Perivascular mast cells regulate vein graft neointimal formation and remodeling.

Objective. Emerging evidence suggests an important role for mast cells in vein graft failure. This study addressed the hypothesis that perivascular mast cells regulate in situ vascular inflammatory and proliferative responses and subsequent vein graft neointimal lesion formation, using an optimized local mast cell reconstitution method.

The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension.

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease.

Improving arteriovenous fistula patency: Transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation.

Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood.

Mast cells and vascular diseases.

Mast cells are increasingly being recognized as effector cells in many cardiovascular conditions. Many mast-cell-derived products such as tryptase and chymase can, through their enzymic action, have detrimental effects on blood vessel structure while mast cell-derived mediators such as cytokines and chemokines can perpetuate vascular inflammation. Mice lacking mast cells have been developed and these are providing an insight into how mast cells are involved in cardiovascular diseases and, as knowledge increase, mast cells may become a viable therapeutic target to slow progression of cardiovascular disease.

Succinobucol-eluting stents increase neointimal thickening and peri-strut inflammation in a porcine coronary model.

Objective: The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model.

Background: Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties.

The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease.

Background: The effect of reactive oxygen species (ROS) on platelet function in coronary heart disease (CHD) is complex and poorly defined. Platelet aggregation studies in healthy volunteers have demonstrated contrasting results when platelets are exposed to ROS. We investigated the effect of ROS on whole blood aggregation (WBA) and the endothelial cell-platelet interaction in patients with CHD.

Low-dose fluvastatin reverses the hypoxic pulmonary adventitial fibroblast phenotype in experimental pulmonary hypertension.

Hypoxic pulmonary hypertension is a worldwide public health problem. Statins attenuate hypoxic pulmonary hypertension in animal models, but the mechanism of action and applicability of these results to human treatment are not established. In hypoxic models, pulmonary artery fibroblast proliferation contributes substantially to pulmonary vascular remodeling.

Tissue localization of nanoparticles is altered due to hypoxia resulting in poor efficacy of curcumin nanoparticles in pulmonary hypertension.

The present study is an attempt to leverage therapeutic benefits of curcumin in pulmonary hypertension by encapsulating it in biodegradable poly(lactide-co-glycolic) acid nanoparticles. Pulmonary hypertension is induced in experimental animals by subjecting them to chronic hypoxic conditions. The ability of curcumin encapsulated nanoparticles to manage pulmonary hypertension is measured by right ventricular hypertrophy, haematocrit, vascular remodelling and target tissue levels of curcumin.

Protective effects of nanoparticulate coenzyme Q10 and curcumin on inflammatory markers and lipid metabolism in streptozotocin-induced diabetic rats: a possible remedy to diabetic complications.

Diabetes and its complications have been linked to increased levels of free radicals and systemic pro-inflammatory cytokines and to an altered lipid profile. Coenzyme Q10 and curcumin are potent antioxidants and anti-inflammatory agents but are underutilized clinically because of their poor bioavailability when administered orally. We have recently developed poly(D,L-lactic-co-glycolic acid)-based nanoparticles in which we have encapsulated coenzyme Q10 and curcumin to increase the oral bioavailability and therapeutic efficacy of the antioxidant molecules.

Threshold of peroxynitrite cytotoxicity in bovine pulmonary artery endothelial and smooth muscle cells.

Peroxynitrite is widely reported as highly cytotoxic; yet recent evidence indicates that at certain concentrations, it can induce pulmonary cell hyper-proliferation and tissue remodelling. This study aimed to establish the threshold concentration of peroxynitrite to induce functional impairment of bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC). PAEC or PASMC were exposed to solution of peroxynitrite or 3-morpholinosydnonimine (SIN-1).

Acute hypoxia stimulates intracellular peroxynitrite formation associated with pulmonary artery smooth muscle cell proliferation.

There is separate evidence for peroxynitrite formation and hypoxia-induced cell proliferation in several models of hypoxic pulmonary hypertension. We therefore hypothesized that the stimulation of pulmonary artery smooth muscle cells (PASMCs) proliferation by hypoxia is due to peroxynitrite formation. The effect of hypoxia alone and in combination with ≤ 0.

Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties.

Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH(4)) contribute to impaired vasodilation in pulmonary hypertension. Due to the chemically unstable nature of BH(4), it was hypothesised that oxidatively stable analogues of BH(4) would be able to support NO synthesis to improve endothelial dysfunction in pulmonary hypertension. Two analogues of BH(4), namely 6-hydroxymethyl pterin (HMP) and 6-acetyl-7,7-dimethyl-7,8-dihydropterin (ADDP), were evaluated for vasodilator activity on precontracted rat pulmonary artery rings.

Inhibition of inducible nitric oxide synthase promotes vein graft neoadventitial inflammation and remodelling.

Background: Grafting veins into the arterial circulation causes endothelial damage and neointimal hyperplasia. However, the remodelling of vein grafts and the contribution of the endothelium is not well understood. Since nitric oxide (NO) has a crucial role in vascular function, we investigated the importance of NO synthases (NOSs) in vein graft re-endothelialization and remodelling in this study.

Towards a self-reporting coronary artery stent--measuring neointimal growth associated with in-stent restenosis using electrical impedance techniques.

Implantable medical devices have become the standard method for treating a variety of cardiovascular diseases (NICE, 2003, 2009), such as coronary artery disease, where coronary artery stents are the device of choice (Fischman et al., 1994; Babapulle et al., 2004).

Pharmacotherapy to improve outcomes in infrainguinal bypass graft surgery: a review of current treatment strategies.

A total of 12,000 infrainguinal bypass grafts are performed annually in the United Kingdom, with outcomes suboptimal: 20% of above-knee vein grafts require intervention by 3 years. Transatlantic Inter-Society Consensus (TASC) guidelines exist on pharmacological management of peripheral vascular disease patients, however, little is recommended regarding optimum pharmacological management following revascularization to improve graft patency. The current recommendation is that all patients are on an antiplatelet agent following bypass grafting, the only intervention with significant evidence supporting use.

Activation of prostanoid EP receptors by prostacyclin analogues in rabbit iliac artery: implications for anti-restenotic potential.

Prostacyclin analogues have the potential to be effective agents in a new generation of drug-eluting stents by virtue of prostanoid IP receptor mediated anti-proliferative effects on smooth muscle cells. However, prostanoid IP receptor mediated vessel relaxation is reduced at elevated analogue concentrations. The mechanisms underlying this loss of activity are unclear, and its influence on the anti-proliferative potential of these compounds remains to be determined.

In situ detection of pterins by SERS.

Surface enhanced Raman scattering (SERS) has been used to detect specific pterin molecules at sub-nanomolar concentrations. SERS is fast becoming a widely used technique for the sensitive and specific detection of multiple analytes. The information-rich and concentration-dependent spectra obtained from SERS make the technique ideally placed for high speed, low cost analysis of almost any analyte.

Modelling drug-eluting stents.

In this study, we consider a family of mathematical models to describe the elution of drug from polymer-coated stents into the arterial wall. Our models include the polymer layer, the media, the adventitia, a possible topcoat polymer layer and atherosclerotic plaque. We investigate the relative importance of transmural convection, diffusion and drug-dependent parameters in drug delivery and deposition.

The sphingosine kinase inhibitor N,N-dimethylsphingosine inhibits neointimal hyperplasia.

Background And Purpose: Sphingosine-1-phosphate and its receptors may be involved in vascular smooth muscle cell (VSMC) proliferation following vascular injury. Here, we evaluate the effect of d-erythro-N,N-dimethylsphingosine (DMS), a sphingosine kinase (SK) inhibitor, on VSMC proliferation, apoptosis and neointimal formation.

Experimental Approach: Growth responses in vitro to fetal calf serum (FCS) were measured by [(3)H]-thymidine incorporation and extracellular signal-regulated kinase-1/2 (ERK-1/2) activation in quiescent primary cultures of porcine VSMC in the presence and absence of various concentrations of the SK inhibitor DMS.

Understanding organic nitrates--a vein hope?

The organic nitrate drugs, such as glyceryl trinitrate (GTN; nitroglycerin), are clinically effective in angina because of their dilator profile in veins and arteries. The exact mechanism of intracellular delivery of nitric oxide (NO), or another NO-containing species, from these compounds is not understood. However, mitochondrial aldehyde dehydrogenase (mtALDH) has recently been identified as an organic nitrate bioactivation enzyme.

Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction.

Hypoxia-induced endothelial dysfunction plays a crucial role in the pathogenesis of hypoxic pulmonary hypertension. p38 MAPK expression is increased in the pulmonary artery following hypoxic exposure. Recent evidence suggests that increased p38 MAPK activity is associated with endothelial dysfunction.

Selective arterial dilatation by glyceryl trinitrate is not associated with nitric oxide formation in vitro.

Aims: Glyceryl trinitrate (GTN) is the most commonly used anti-anginal agent, yet its mechanism of action has still to be fully established. Release of nitric oxide (NO) and the selectivity of GTN in the venous system are believed to be crucial to this drug's anti-anginal action.

Methods: Rat superior mesenteric arteries and renal veins were mounted in a wire myograph with an intraluminal NO microsensor.