Simon Kennedy

University of Glasgow, Glasgow, Scotland, United Kingdom

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Publications (48)185.89 Total impact

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    ABSTRACT: The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. This study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodeling processes. Vascular injury was induced in C57BL/6 mice and high fat fed ApoE-/- mice by wire denudation and ligation of the left carotid artery. Neointimal and medial composition was assessed using immunohistochemistry and electrospray mass spectrometry. Primary rabbit aortic SMCs were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio was significantly larger in wire-injured ApoE-/- mice (3.62 ± 0.49 vs. 0.83 ± 0.25 in C57BL/6 mice, n=3) and there was increased oxidized LDL (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines were also observed in wire-injured ApoE-/- carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration while chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum (154.8 ± 14.2% of viable cells at 1 µM PGPC vs. control, n=6). In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.
    Clinical science (London, England : 1979). 12/2014;
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    ABSTRACT: Perivascular adipose tissue (PVAT) is an active endocrine and paracrine organ that modulates vascular function, with implications for the pathophysiology of cardiovascular disease (CVD). Adipocytes and stromal cells contained within PVAT produce mediators (adipokines, cytokines, reactive oxygen species and gaseous compounds) with a range of paracrine effects modulating vascular smooth muscle cell contraction, proliferation and migration. However, the modulatory effect of PVAT on the vascular system in diseases, such as obesity, hypertension and atherosclerosis, remains poorly characterized. AMP-activated protein kinase (AMPK) regulates adipocyte metabolism, adipose biology and vascular function, and hence may be a potential therapeutic target for metabolic disorders such as type 2 diabetes mellitus (T2DM) and the vascular complications associated with obesity and T2DM. The role of AMPK in PVAT or the actions of PVAT have yet to be established, however. Activation of AMPK by pharmacological agents, such as metformin and thiazolidinediones, may modulate the activity of PVAT surrounding blood vessels and thereby contribute to their beneficial effect in cardiometabolic diseases. This review will provide a current perspective on how PVAT may influence vascular function via AMPK. We will also attempt to demonstrate how modulating AMPK activity using pharmacological agents could be exploited therapeutically to treat cardiometabolic diseases.
    British Journal of Pharmacology 02/2014; 171(3):595-617. · 5.07 Impact Factor
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    ABSTRACT: The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration-response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.
    Pulmonary Pharmacology &amp Therapeutics 01/2014; · 2.54 Impact Factor
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    ABSTRACT: Objectives Relaxation of vascular smooth muscle (VSM) requires re-uptake of cytosolic Ca2+ into the sarcoplasmic reticulum (SR) via the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA), or extrusion via the Plasma Membrane Ca2+ ATPase (PMCA) or sodium Ca2+ exchanger (NCX). Peroxynitrite, a reactive species formed in vascular inflammatory diseases, upregulates SERCA activity to induce relaxation but, chronically, can contribute to atherogenesis and altered vascular function by escalating endoplasmic reticulum stress. Our objectives were to determine if peroxynitrite-induced relaxation and Ca2+ handling processes within vascular smooth muscle cells were altered as atherosclerosis develops. Methods Aortae from control and ApoE−/− mice were studied histologically, functionally and for protein expression levels of SERCA and PMCA. Ca2+ responses were assessed in dissociated aortic smooth muscle cells in the presence and absence of extracellular Ca2+. Results Relaxation to peroxynitrite was concentration-dependent and endothelium-independent. The abilities of the SERCA blocker thapsigargin and the PMCA inhibitor carboxyeosin to block this relaxation were altered during fat feeding and plaque progression. SERCA levels were progressively reduced, while PMCA expression was upregulated. In ApoE−/− VSM cells, increases in cytosolic Ca2+ [Ca2+]c in response to SERCA blockade were reduced, while SERCA-independent Ca2+ clearance was faster compared to control. Conclusion As atherosclerosis develops in the ApoE−/− mouse, expression and function of Ca2+ handling proteins are altered. Up-regulation of Ca2+ removal via PMCA may offer a potential compensatory mechanism to help normalise the dysfunctional relaxation observed during disease progression.
    Atherosclerosis 01/2014; 234(1):154–161. · 3.71 Impact Factor
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    ABSTRACT: AimsThe long-term failure of autologous saphenous vein bypass grafts due to neointimal thickening is a major clinical burden. Identifying novel strategies to prevent neointimal thickening is important. Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.Methods and resultsWe undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model. These profiling experiments identified a number of miRNAs which were dysregulated following engraftment. miR-21 levels were substantially elevated following engraftment and these results were confirmed by quantitative real-time PCR in mouse, pig, and human models of vein graft neointimal formation. Genetic ablation of miR-21 in mice or grafted veins dramatically reduced neointimal formation in a mouse model of vein grafting. Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.Conclusion This is the first report demonstrating that miR-21 plays a pathological role in vein graft failure. Furthermore, we also provided evidence that knockdown of miR-21 has therapeutic potential for the prevention of pathological vein graft remodelling.
    European Heart Journal 03/2013; · 14.72 Impact Factor
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    ABSTRACT: 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.
    Pharmacology [?] Therapeutics 01/2013; · 7.79 Impact Factor
  • Marie-Ann Ewart, Simon Kennedy
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    ABSTRACT: Cardiovascular complications are the leading cause of death and morbidity in patients with diabetes; accounting for around 7 out of 10 of all causes of death in this population. Returning patients to normoglycaemia alone has been shown to have little effect on cardiovascular end points, therefore new therapies and strategies are required in order to reduce the incidence and improve outcomes of cardiovascular disease in diabetic individuals. The metabolic enzyme AMP-activated protein kinase (AMPK) has emerged in recent years as an attractive potential therapeutic target for diabetic vascular disease, and studies have shown improved endothelial and smooth muscle cell function following AMPK activation. Additionally, improved lipid profiles, reduced hypertrophic cardiomyocyte growth and protection from cardiac ischaemia-reperfusion injury have also been observed as beneficial outcomes of AMPK therapy. In this review we will discuss in detail the potential downstream targets of AMPK activation in the cardiovascular system. We will also provide an overview of long-known and newly discovered direct and indirect AMPK activators, as well as novel synthesised AMPK-activating compounds, which will highlight the potential for further exploiting AMPK in a therapeutic context for cardiovascular disease in diabetes.
    Cardiovascular & hematological agents in medicinal chemistry 05/2012; 10(3):190-211.
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    ABSTRACT: 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. METHODS: Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES) or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS). RESULTS: The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days). 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES and 0.36 ± 0.17 mm for SucRES (p < 0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (p < 0.05), whereas RES reduced inflammation compared with BMS (p < 0.05). CONCLUSION: In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting. © 2012 Wiley Periodicals, Inc.
    Catheterization and Cardiovascular Interventions 05/2012; · 2.51 Impact Factor
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    ABSTRACT: 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. ROS generated by xanthine and xanthine oxidase caused a concentration-dependent inhibition of WBA in blood from healthy donors and patients with CHD. In patients with CHD, 100 μM xanthine and 100 mU/ml xanthine oxidase inhibited WBA in response to 3 μg/ml collagen by 28.9% (95% CI 15.9%-41.8%, p<0.001) and in response to 5 μM ADP by 36.0% (95% CI 9.6%-62.4%, p=0.005). Using nitrotyrosine expression, platelets isolated from patients with CHD were found to be susceptible to peroxynitrite damage. The addition of 1 × 10(5) cultured endothelial cells inhibited WBA in response to 3 μg/ml collagen by 31.2% (95% CI 12.2%-50.2%, p<0.05) and in response to 5 μM ADP by 31.6% (95% CI 2.5-60.7%, p<0.05). Addition of xanthine and xanthine oxidase did not alter this effect, however pre-treatment of endothelial cells with a nitric oxide synthase inhibitor (L-NAME) partly reversed the inhibition. ROS inhibit WBA in blood from patients with CHD. Whilst endothelial cells also inhibit WBA, the effect is attenuated by L-NAME, suggesting that nitric oxide is likely to remain an important protective mechanism against thrombosis in CHD.
    Thrombosis Research 04/2012; 130(2):210-5. · 3.13 Impact Factor
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    ABSTRACT: Oxidized phospholipids, such as the products of the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by nonenzymatic radical attack, are known to be formed in a number of inflammatory diseases. Interest in the bioactivity and signaling functions of these compounds has increased enormously, with many studies using cultured immortalized and primary cells, tissues, and animals to understand their roles in disease pathology. Initially, oxidized phospholipids were viewed largely as culprits, in line with observations that they have proinflammatory effects, enhancing inflammatory cytokine production, cell adhesion and migration, proliferation, apoptosis, and necrosis, especially in vascular endothelial cells, macrophages, and smooth muscle cells. However, evidence has emerged that these compounds also have protective effects in some situations and cell types; a notable example is their ability to interfere with signaling by certain Toll-like receptors (TLRs) induced by microbial products that normally leads to inflammation. They also have protective effects via the stimulation of small GTPases and induce up-regulation of antioxidant enzymes and cytoskeletal rearrangements that improve endothelial barrier function. Oxidized phospholipids interact with several cellular receptors, including scavenger receptors, platelet-activating factor receptors, peroxisome proliferator-activated receptors, and TLRs. The various and sometimes contradictory effects that have been observed for oxidized phospholipids depend on their concentration, their specific structure, and the cell type investigated. Nevertheless, the underlying molecular mechanisms by which oxidized phospholipids exert their effects in various pathologies are similar. Although our understanding of the actions and mechanisms of these mediators has advanced substantially, many questions do remain about their precise interactions with components of cell signaling pathways.
    Free Radical Biology and Medicine 10/2011; 52(2):266-80. · 5.27 Impact Factor
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    ABSTRACT: We have previously demonstrated that bindarit, a selective inhibitor of monocyte chemotactic proteins (MCPs), is effective in reducing neointimal formation in rodent models of vascular injury by reducing smooth muscle cell proliferation and migration and neointimal macrophage content, effects associated with the inhibition of MCP-1/CCL2 production. The aim of the current study was to evaluate the efficacy of bindarit on in-stent stenosis in the preclinical porcine coronary stent model. One or 2 bare metal stents (Multi-Link Vision, 3.5 mm) were deployed (1:1.2 oversize ratio) in the coronary arteries of 42 pigs (20 bindarit versus 22 controls). Bindarit (50 mg/kg per day) was administered orally from 2 days before stenting until the time of euthanasia at 7 and 28 days. Bindarit caused a significant reduction in neointimal area (39.4%, P<0.001, n=9 group), neointimal thickness (51%, P<0.001), stenosis area (37%, P<0.001), and inflammatory score (40%, P<0.001) compared with control animals, whereas there was no significant difference in the injury score between the 2 groups. Moreover, treatment with bindarit significantly reduced the number of proliferating cells (by 45%, P<0.05; n=6 group) and monocyte/macrophage content (by 55%, P<0.01; n=5-6 group) in stented arteries at day 7 and 28, respectively. These effects were associated with a significant (P<0.05) reduction of MCP-1 plasma levels at day 28. In vitro data showed that bindarit (10-300 μmol/L) reduced tumor necrosis factor-α (50 ng/mL)-induced pig coronary artery smooth muscle cell proliferation and inhibited MCP-1 production. Our results show the efficacy of bindarit in the prevention of porcine in-stent stenosis and support further investigation for clinical application of this compound.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2011; 31(11):2448-54. · 6.34 Impact Factor
  • Marie-Ann Ewart, Simon Kennedy
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    ABSTRACT: AMP-activated protein kinase (AMPK) is proposed to be a key regulator of cellular and organismal metabolism and has reported vasculoprotective effects. In addition, many therapeutic agents used in the treatment of diabetes and atherosclerosis such as metformin, thiazolidinediones and statins may exert their vasculoprotective effects through activation of AMPK. Activation of AMPK has a number of potentially beneficial anti-atherosclerotic effects including reducing adhesion of inflammatory cells to the blood vessel endothelium, reducing lipid accumulation and the proliferation of inflammatory cells caused by oxidised lipids, stimulation of gene expression responsible for cellular antioxidant defenses and stimulation of enzymes responsible for nitric oxide formation. In humans and animals the AMPK cascade triggers vascular protective mechanisms that have been shown to reduce myocardial ischaemic injury and mutations in AMPK can cause familial hypertrophic cardiomyopathy. Taken together, these data suggest that activation and function of AMPK contributes to cardiovascular health. In this review we propose to focus on the vasculoprotective effects of AMPK, the evidence for AMPK activation with currently used therapeutic agents and the potential for agents which specifically activate AMPK as a treatment for vascular disease.
    Pharmacology [?] Therapeutics 11/2010; 131(2):242-53. · 7.79 Impact Factor
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    ABSTRACT: 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). One post-operative problem with these devices is the long-term monitoring of the device-tissue interface, with respect to the complications that often arise from in-stent restenosis. This monitoring, where it is available, is currently performed using imaging techniques such as contrast angiography, IVUS, CT and MRI. In this study we propose an alternative method for the non-invasive monitoring of restenosis in coronary artery stents. This preliminary study uses impedance spectroscopy to measure the electrical impedance of cells and tissues associated with the neointimal growth that characterises in-stent restenosis in coronary artery stents. An in vitro organ culture model, using a stent implanted in a section of pig coronary artery, simulated tissue growth inside a stent. Impedance measurements were made regularly over a 28-day culture period. In a novel step, the stent itself was employed as an electrode. Differences in electrical impedance could be seen between control (stent alone) and artery-embedded stents in culture, which were associated with the presence of biological tissue. This method could potentially be developed to produce a stent that was capable of self-reporting in-stent restenosis. The advantages of such a device would be that monitoring could be non-invasively and easily carried out, allowing more routine follow-ups and the early identification and management of any device complications.
    Biosensors & Bioelectronics 10/2010; 26(2):661-6. · 6.45 Impact Factor
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    ABSTRACT: The activation of nuclear factor-κB (NF-κB) is a crucial step in the arterial wall's response to injury. The identification and characterization of the NF-κB essential modulator-binding domain (NBD) peptide, which can block the activation of the IκB kinase complex, have provided an opportunity to selectively abrogate the inflammation-induced activation of NF-κB. The aim of the present study was to evaluate the effect of the NBD peptide on neointimal formation. In the rat carotid artery balloon angioplasty model, local treatment with the NBD peptide (300 μg/site) significantly reduced the number of proliferating cells at day 7 (by 40%; P<0.01) and reduced injury-induced neointimal formation (by 50%; P<0.01) at day 14. These effects were associated with a significant reduction of NF-κB activation and monocyte chemotactic protein-1 expression in the carotid arteries of rats treated with the peptide. In addition, the NBD peptide (0.01 to 1 μmol/L) reduced rat smooth muscle cell proliferation, migration, and invasion in vitro. Similar results were observed in apolipoprotein E(-/-) mice in which the NBD peptide (150 μg/site) reduced wire-induced neointimal formation at day 28 (by 47%; P<0.01). The NBD peptide reduces neointimal formation and smooth muscle cell proliferation/migration, both effects associated with the inhibition of NF-κB activation.
    Arteriosclerosis Thrombosis and Vascular Biology 10/2010; 30(12):2458-66. · 6.34 Impact Factor
  • Junxi Wu, Roger M Wadsworth, Simon Kennedy
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    ABSTRACT: 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. Mouse isogenic vena cava was grafted into the carotid artery. Progressive remodelling of the grafted veins was evidenced by re-endothelialization at 2 weeks and subsequent appearance of vasomotor function at 4 weeks. Pharmacological inhibition of inducible NOS (iNOS) with the specific inhibitor 1400W, administered between 2 and 4 weeks after grafting, when re-endothelialization was complete, resulted in neoadventitial inflammation, neoadventitial thickening and impaired functional remodelling. Completion of re-endothelialization is pivotal in vein graft remodelling in the mouse and is associated with a series of changes in inflammation, proliferation and initiation of vascular functional remodelling. After re-endothelialization, iNOS upregulation may be an important mechanism to prevent secondary neoadventitial inflammation and preserve ongoing functional remodelling. iNOS activity could therefore be beneficial for long-term patency of the vein graft.
    Journal of Vascular Research 10/2010; 48(2):141-9. · 2.43 Impact Factor
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    ABSTRACT: Anandamide and sphingosine-1-phosphate (S1P) both regulate vascular tone in a variety of vessels. This study aimed to examine the mechanisms involved in the regulation of coronary vascular tone by anandamide and S1P, and to determine whether any functional interaction occurs between these receptor systems. Mechanisms used by anandamide and S1P to regulate rat coronary artery (CA) reactivity were investigated using wire myography. Interactions between S1P and the cannabinoid (CB)(2) receptor were determined using human embryonic kidney 293 (HEK293) cells that stably over-express recombinant CB(2) receptor. Anandamide and S1P induced relaxation of the rat CA. CB(2) receptor antagonists attenuated anandamide-induced relaxation, while S1P-mediated relaxation was dependent on the vascular endothelium and S1P(3). Anandamide treatment resulted in an increase in the phosphorylation of sphingosine kinase-1 within the CA. Conversely, anandamide-mediated relaxation was attenuated by inhibition of sphingosine kinase. Moreover, S1P(3), specifically within the vascular endothelium, was required for anandamide-mediated vasorelaxation. In addition to this, S1P-mediated relaxation was also reduced by CB(2) receptor antagonists and sphingosine kinase inhibition. Further evidence that S1P functionally interacts with the CB(2) receptor was also observed in HEK293 cells over-expressing the CB(2) receptor. In the vascular endothelium of rat CA, anandamide induces relaxation via a mechanism requiring sphingosine kinase-1 and S1P/S1P(3). In addition, we report that S1P may exert some of its effects via a CB(2) receptor- and sphingosine kinase-dependent mechanism, where subsequently formed S1P may have privileged access to S1P(3) to induce vascular relaxation.
    British Journal of Pharmacology 09/2010; 161(1):176-92. · 5.07 Impact Factor
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    ABSTRACT: 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. A classical organ bath approach was used to examine the functional response of the rabbit iliac artery to the prostacyclin analogues, AFP-07 and cicaprost. Selective receptor antagonists for prostanoid IP (RO-1138452), EP(1) (SC-51322) and EP(3) (L-798106) receptors were used to characterise the receptors involved. The effects of these agents on proliferation ([(3)H]-thymidine incorporation) of rabbit iliac artery smooth muscle cells stimulated by foetal calf serum were then studied. AFP-07 gave a bell-shaped log concentration-response curve consisting of prostanoid IP receptor mediated relaxation followed by reversal at higher concentrations. SC-51322 and L-798106 potentiated this relaxation, although only L-798106 completely removed the contractile element. The prostanoid EP(3) receptor agonist, sulprostone, produced constriction, which was attenuated by L-798106. RO-1138452 blocked the inhibitory action of AFP-07 and cicaprost on proliferation, implicating an involvement of prostanoid IP receptors. L-798106 had no effect on the anti-proliferative effect of cicaprost, but reduced the effect of AFP-07. Non-selective activation of prostanoid EP(3) receptors (and possibly prostanoid EP(1) receptors) compromises the relaxant activity of prostacyclin analogues, although it does not reduce the anti-proliferative capacity of these compounds in the model studied.
    European journal of pharmacology 05/2010; 641(2-3):160-7. · 2.59 Impact Factor
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
  • Biophysical Journal 01/2010; 98(3). · 3.67 Impact Factor
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    David G S Farmer, Simon Kennedy
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    ABSTRACT: Evidence provided by both clinical and pre-clinical studies regarding a central involvement of the receptor for advanced glycation endproducts (RAGE) in vascular disease continues to mount. RAGE is upregulated as a consequence of activation of the ubiquitous pro-inflammatory transcription factor NF-kappaB which is activated in response to diverse inflammatory stimuli including hyperglycaemia, oxidised low density lipoprotein (oxLDL) and reduced shear stress. RAGE may maintain and amplify inflammatory responses in the vasculature if ligand for the receptor is present. RAGE binding by circulating advanced glycation endproducts (AGEs) or S100 protein released by activated leukocytes results in the generation of reactive oxygen species (ROS) and further activation of NF-kappaB. This leads to upregulation of adhesion molecules for circulating monocytes as well as further upregulation of RAGE itself. In addition, these ROS may scavenge and reduce bioavailability of the labile vasodilator nitric oxide (NO), reducing its anti-inflammatory effects and possibly compromising control of vascular tone directly. In addition to atherosclerosis and vascular diseases associated with diabetes, recent data from studies in transgenic mice overexpressing the RAGE ligand S100A4/MTS1 suggest a role for RAGE in the pathogenesis of pulmonary arterial hypertension (PAH). RAGE antagonism also prevents proliferation and migration of pulmonary arterial smooth muscle cells in response to 5-HT, suggesting that S100-RAGE signalling may be of key importance in pulmonary vascular homeostasis and/or disease. Further study of the role of RAGE in inflammation seems likely to yield, not only promising therapeutics but key insights into the pathophysiology of vascular disease as well.
    Pharmacology [?] Therapeutics 08/2009; 124(2):185-94. · 7.79 Impact Factor

Publication Stats

338 Citations
185.89 Total Impact Points

Institutions

  • 2007–2014
    • University of Glasgow
      • Institute of Cardiovascular and Medical Sciences
      Glasgow, Scotland, United Kingdom
  • 1998–2012
    • University of Strathclyde
      • Strathclyde Institute of Pharmacy and Biomedical Sciences
      Glasgow, SCT, United Kingdom