327 results on '"Jeremy JY"'
Search Results
2. Letters to the Editor
- Author
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Dimitri P. Mikhailidis, Milionis Hj, and Jeremy Jy
- Subjects
medicine.medical_specialty ,business.industry ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Intima-media thickness ,Internal medicine ,Cardiology ,Medicine ,030212 general & internal medicine ,Endothelial dysfunction ,Cardiology and Cardiovascular Medicine ,business - Published
- 1999
3. Characterization of the Differential Response of Endothelial Cells Exposed to Normal and Elevated Laminar Shear Stress
- Author
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White, SJ, Hayes, EM, Lehoux, S, Jeremy, JY, Horrevoets, AJG, Newby, AC, White, SJ, Hayes, EM, Lehoux, S, Jeremy, JY, Horrevoets, AJG, and Newby, AC
- Abstract
Most acute coronary events occur in the upstream region of stenotic atherosclerotic plaques that experience laminar shear stress (LSS) elevated above normal physiological levels. Many studies have described the atheroprotective effect on endothelial behavior of normal physiological LSS (approximately 15 dynes/cm2) compared to static or oscillatory shear stress (OSS), but it is unknown whether the levels of elevated shear stress imposed by a stenotic plaque would preserve, enhance or reverse this effect. Therefore we used transcriptomics and related functional analyses to compare human endothelial cells exposed to laminar shear stress of 15 (LSS15-normal) or 75 dynes/cm2 (LSS75-elevated). LSS75 upregulated expression of 145 and downregulated expression of 158 genes more than twofold relative to LSS15. Modulation of the metallothioneins (MT1-G, -M, -X) and NADPH oxidase subunits (NOX2, NOX4, NOX5, and p67phox) accompanied suppression of reactive oxygen species production at LSS75. Shear induced changes in dual specificity phosphatases (DUSPs 1, 5, 8, and 16 increasing and DUSPs 6 and 23 decreasing) were observed as well as reduced ERK1/2 but increased p38 MAP kinase phosphorylation. Amongst vasoactive substances, endothelin-1 expression decreased whereas vasoactive intestinal peptide (VIP) and prostacyclin expression increased, despite which intracellular cAMP levels were reduced. Promoter analysis by rVISTA identified a significant over representation of ATF and Nrf2 transcription factor binding sites in genes upregulated by LSS75 compared to LSS15. In summary, LSS75 induced a specific change in behavior, modifying gene expression, reducing ROS levels, altering MAP kinase signaling and reducing cAMP levels, opening multiple avenues for future study.
- Published
- 2011
4. The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.
- Author
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Morcos, SK, Dawson, P, Pearson, JD, Jeremy, JY, Davenport, AP, Yates, MS, Tirone, P, Cipolla, P, de Haen, C, Muschick, P, Krause, W, Refsum, H, Emery, CJ, Liss, P, Nygren, A, Haylor, J, Pugh, ND, Karlsson, JO, Morcos, SK, Dawson, P, Pearson, JD, Jeremy, JY, Davenport, AP, Yates, MS, Tirone, P, Cipolla, P, de Haen, C, Muschick, P, Krause, W, Refsum, H, Emery, CJ, Liss, P, Nygren, A, Haylor, J, Pugh, ND, and Karlsson, JO
- Published
- 1999
5. Biodegradable External Stents Inhibit Saphenous Vein Graft Thickening in the Pig
- Author
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Gadsdon, P, primary, Bulbulia, R, additional, Smith, FCT, additional, Angelini, GD, additional, and Jeremy, JY, additional
- Published
- 2002
- Full Text
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6. Circulating Homocysteine and Copper Following Coronary Artery Bypass Graft Surgery with and Without Cardiopulmonary Bypass
- Author
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Shukla, N, primary, Jeremy, JY, additional, Handley, A, additional, Talpahewa, SP, additional, Capoun, R, additional, Angelini, GD, additional, and Ascoine, R, additional
- Published
- 2002
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7. Heat Shock Protein (65 kDa) – Stimulated Proliferation of Human Saphenous Vein Smooth Muscle Cells is Inhibited by Thapsigargin
- Author
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Shukla, N, primary, Chan, YC, additional, Stansby, G, additional, Singh, M, additional, Stanford, J, additional, and Jeremy, JY, additional
- Published
- 2002
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8. Oxygen free radicals and the penis
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Minhas, S, primary, Jeremy, JY, additional, Jones, RWA, additional, Ralph, D, additional, Rees, RW, additional, and Persad, RA, additional
- Published
- 2002
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9. Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed by in vitro allergen exposure in bronchial asthma
- Author
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Spiteri, MA, primary, Knight, RA, additional, Jeremy, JY, additional, Barnes, PJ, additional, and Chung, KF, additional
- Published
- 1994
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10. The role of Protein Kinases in Mediating Calcium Uptake by Human Platelets
- Author
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Gill, J, primary, Jeremy, JY, additional, Mikhaildis, DP, additional, and Winder, AF, additional
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- 1993
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11. Adrenoceptor-Linked [45Ca2+] Uptake in Platelets from Diabetic Rats
- Author
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Gill, J, primary, Jeremy, JY, additional, Mikhailidis, DP, additional, and Thompson, CS, additional
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- 1992
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12. Lisinopril and nifedipine administration inhibits the ex vivo uptake of [45Ca2+] by platelets from hypertensive diabetic patients.
- Author
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Gill, J, primary, Fonseca, V, additional, Dandona, P, additional, and Jeremy, JY, additional
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- 1992
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13. Plasma 6-keto-PGF1alpha, thromboxane B2 and PGE2 during diabetic ketoacidosis
- Author
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Jeremy, JY, primary, Barradas, MA, additional, and Mikhailidis, DP, additional
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- 1990
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14. Intraplatelet Substances in Renal Disease
- Author
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Barradas, MA, primary, Fonseca, VA, additional, Gill, DS, additional, Jeremy, JY, additional, Varghese, Z., additional, Balliod, R., additional, Moorhead, JF, additional, and Dandona, P., additional
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- 1990
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15. Eicosanoids, impotence and pharmacologically induced erection
- Author
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Mikhailidis, DP, primary, Jeremy, JY, additional, Shoukry, K, additional, and Virag, R, additional
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- 1990
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16. Adrenoceptor-Linked [45Ca2+] Uptake in Patients with Anorexia Nervosa
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Gill, J, primary, D'Souza, V, additional, Jeremy, JY, additional, Wakeling, A, additional, and Dandona, P, additional
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- 1990
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17. Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172).
- Author
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Mikhailidis, DP, Fonseca, VA, Barradas, MA, Jeremy, JY, and Dandona, P
- Abstract
1. The effects of an intravenous injection of a conventional high molecular weight heparin (HMWH) were compared with those of a low molecular weight heparinoid (Org 10172). A bolus injection of HMWH (5000 iu) was associated with: (a) a small but significant prolongation of bleeding time (BT); (b) a significant fall in PRP platelet count; (c) significantly enhanced platelet aggregation; and (d) significantly increased platelet thromboxane A2 (TXA2) release. These changes were not observed following the intravenous injection of Org 10172 (3200 anti Xa U). 2. These experiments were repeated following the oral administration of acetylsalicylic acid (ASA). HMWH again caused some enhancement of platelet aggregation despite the ASA-mediated inhibition of platelet aggregation and TXA2 release. Administration of Org 10172 to subjects taking ASA did not alter any of the platelet function indices. 3. In additional control experiments the injection of 5000 iu of HMWH was associated with a significant fall in PRP but not whole blood platelet counts. This finding suggests that the fall in PRP platelet count is a methodological artefact. 4. The HMWH also induced a significantly greater increase in serum non-esterified fatty acid (NEFA) concentrations than Org 10172. 5. The present findings indicate that Org 10172 is a less potent stimulator of platelet aggregation and lipolysis than HMWH. 6. The minor prolongation of the BT after HMWH is not compatible with enhanced aggregation but may be a consequence of alterations in the activity of coagulation factors and vascular- platelet interactions or of ongoing platelet activation accompanied by granule depletion. 7. The different effects of the two anticoagulants assessed suggests a therapeutic advantage in favour of Org 10172, especially in patients with hyperactive platelets. [ABSTRACT FROM AUTHOR]
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- 1987
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18. Editorial: Phospholipases C and A2 in malignant cell proliferation
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Wickremasinghe Rg and Jeremy Jy
- Subjects
chemistry.chemical_classification ,Cell division ,Phospholipase C ,Cell growth ,Clinical Biochemistry ,hemic and immune systems ,Cell Biology ,respiratory system ,Biology ,Phospholipase ,Molecular biology ,Cell biology ,Enzyme ,Phospholipase A2 ,GTP-binding protein regulators ,chemistry ,cardiovascular system ,biology.protein ,lipids (amino acids, peptides, and proteins) ,tissues ,Gene - Abstract
Phospholipase C et proteine G. Oncogenes ras et Phospholipase C. Role des eicosanoide dans la proliferation cellulaire
- Published
- 1989
19. Ethanol raises prostacyclin in vivo and in vitro [letter]
- Author
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Mikhailidis, DP, primary, Jeremy, JY, additional, Barradas, MA, additional, and Dandona, P, additional
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- 1985
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20. Editorial: The role of prostaglandins, leukotrienes and essential fatty acids in the pathogenesis of the complications associated with diabetes mellitus
- Author
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Mikhailidis, DP, primary, Jeremy, JY, additional, and Dandona, P, additional
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- 1988
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21. Platelet synthesis of cyclooxygenase and lipoxygenase products in type I and type II diabetes
- Author
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Jeremy, JY, primary, Mikhailidis, DP, additional, Barradas, MA, additional, and Dandona, P, additional
- Published
- 1988
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22. Platelet Function in Diabetics and Non-Diabetics following Oral Nisoldipine
- Author
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Hendra, TJ, primary, Oughton, J, additional, Wager, J, additional, Jeremy, JY, additional, Dandona, P, additional, and Yudkin, JS, additional
- Published
- 1988
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23. Effects of verapamil and nisoldipine on human platelets: in vivo and in vitro studies [letter]
- Author
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Jeremy, JY, primary, Barradas, MA, additional, Mikhailidis, DP, additional, and Dandona, P., additional
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- 1986
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24. Editorial: Therapeutic applications of prostanoids and Essential Fatty Acids
- Author
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Mikhailidis, DP, primary, Jeremy, JY, additional, and Dandona, P, additional
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- 1988
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25. Editorial: Platelet function — The role of essential fatty acids and eicosanoids
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Mikhailidis, DP, primary and Jeremy, JY, additional
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- 1989
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26. Sexual dysfunction and cardiac risk (the second Princeton Concensus Conference)
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Jeremy JY, Muzaffar S, Koupparis AJ, Angelini GD, Persad R, and Shukla N
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- 2005
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27. Plasma 6-keto-PGF 1alpha, thromboxane B 2 and PGE 2 during diabetic ketoacidosis
- Author
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Jeremy, JY, Barradas, MA, and Mikhailidis, DP
- Published
- 1990
- Full Text
- View/download PDF
28. Endothelium-Derived Hyperpolarization and Coronary Vasodilation: Diverse and Integrated Roles of Epoxyeicosatrienoic Acids, Hydrogen Peroxide, and Gap Junctions.
- Author
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Ellinsworth DC, Sandow SL, Shukla N, Liu Y, Jeremy JY, and Gutterman DD
- Subjects
- Animals, Calcium Signaling physiology, Humans, Coronary Vessels metabolism, Eicosanoids metabolism, Endothelium, Vascular metabolism, Gap Junctions metabolism, Hydrogen Peroxide metabolism, Muscle, Smooth, Vascular metabolism, Myocardium metabolism, Vasodilation physiology
- Abstract
Myocardial perfusion and coronary vascular resistance are regulated by signaling metabolites released from the local myocardium that act either directly on the VSMC or indirectly via stimulation of the endothelium. A prominent mechanism of vasodilation is EDH of the arteriolar smooth muscle, with EETs and H(2)O(2) playing important roles in EDH in the coronary microcirculation. In some cases, EETs and H(2)O(2) are released as transferable hyperpolarizing factors (EDHFs) that act directly on the VSMCs. By contrast, EETs and H(2)O(2) can also promote endothelial KCa activity secondary to the amplification of extracellular Ca(2+) influx and Ca(2+) mobilization from intracellular stores, respectively. The resulting endothelial hyperpolarization may subsequently conduct to the media via myoendothelial gap junctions or potentially lead to the release of a chemically distinct factor(s). Furthermore, in human isolated coronary arterioles dilator signaling involving EETs and H(2)O(2) may be integrated, being either complimentary or inhibitory depending on the stimulus. With an emphasis on the human coronary microcirculation, this review addresses the diverse and integrated mechanisms by which EETs and H(2)O(2) regulate vessel tone and also examines the hypothesis that myoendothelial microdomain signaling facilitates EDH activity in the human heart., (© 2015 John Wiley & Sons Ltd.)
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- 2016
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29. Wnt5a-induced Wnt1-inducible secreted protein-1 suppresses vascular smooth muscle cell apoptosis induced by oxidative stress.
- Author
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Mill C, Monk BA, Williams H, Simmonds SJ, Jeremy JY, Johnson JL, and George SJ
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- Animals, Apoptosis physiology, Cell Survival drug effects, Cell Survival physiology, Cells, Cultured, Humans, Hydrogen Peroxide pharmacology, Mice, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiopathology, Signal Transduction drug effects, Signal Transduction physiology, TCF Transcription Factors physiology, Wnt Proteins physiology, Wnt-5a Protein, beta Catenin physiology, Apoptosis drug effects, CCN Intercellular Signaling Proteins physiology, Muscle, Smooth, Vascular pathology, Oxidative Stress physiology, Proto-Oncogene Proteins pharmacology, Proto-Oncogene Proteins physiology, Wnt Proteins pharmacology
- Abstract
Objective: Apoptosis of vascular smooth muscle cells (VSMCs) contributes to thinning and rupture of the atherosclerotic plaque fibrous cap and is thereby associated with myocardial infarction. Wnt protein activation of β-catenin regulates numerous genes that are associated with cell survival. We therefore investigated Wnt/β-catenin survival signaling in VSMCs and assessed the presence of this pathway in human atherosclerotic plaques at various stages of the disease process., Approach and Results: Wnt5a induced β-catenin/T-cell factor signaling and retarded oxidative stress (H₂O₂)-induced apoptosis in mouse aortic VSMCs. Quantification of mRNA levels revealed a >4-fold (P<0.05; n=9) increase in the expression of the Wnt/β-catenin responsive gene, Wnt1-inducible secreted protein-1 (WISP-1), which was dependent on cAMP response element-binding protein and sustained in the presence of H₂O₂. Exogenous WISP-1 significantly reduced H₂O₂-induced apoptosis by 43% (P<0.05; n=3) and was shown using silencing small interfering RNA, to be important for Wnt5a-dependent survival responses to H₂O₂ (P<0.05; n=3). WISP-1 protein levels were significantly lower (≈50%) in unstable atherosclerosis compared with stable plaques (n=11 and n=14)., Conclusions: These results indicate for the first time that Wnt5a induces β-catenin survival signaling in VSMCs via WISP-1. The deficiency of the novel survival factor, WISP-1 in intimal VSMCs of unstable coronary plaques, suggests that there is altered Wnt/β-catenin/ T-cell factor signaling with progressive atherosclerosis, and restoration of WISP-1 protein might be an effective stabilization factor for vulnerable atherosclerotic plaques., (© 2014 American Heart Association, Inc.)
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- 2014
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30. Interactions between thromboxane A₂, thromboxane/prostaglandin (TP) receptors, and endothelium-derived hyperpolarization.
- Author
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Ellinsworth DC, Shukla N, Fleming I, and Jeremy JY
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- Animals, Gap Junctions physiology, Humans, Biological Factors metabolism, Prostaglandins metabolism, Receptors, Prostaglandin metabolism, Receptors, Thromboxane metabolism, Thromboxane A2 metabolism
- Abstract
Endothelium-dependent smooth muscle hyperpolarization (EDH) increasingly predominates over endothelium-derived nitric oxide (NO) as a participant in vasodilation as vessel size decreases. Its underlying nature is highly variable between vessel types, species, disease states, and exact experimental conditions, and is variably mediated by one or more transferable endothelium-derived hyperpolarizing factors and/or the electrotonic spread of endothelial hyperpolarization into the media via gap junctions. Although generally regarded (and studied) as a mechanism that is independent of NO and prostanoids, evidence has emerged that the endothelium-derived contracting factor and prostanoid thromboxane A2 can modulate several signalling components central to EDH, and therefore potentially curtail vasodilation through mechanisms that are distinct from those putatively involved in direct smooth muscle contraction. Notably, vascular production of thromboxane A2 is elevated in a number of cardiovascular disease states that promote endothelial dysfunction. This review will therefore discuss the mechanisms through which thromboxane A2 interacts with and modulates EDH, and will also consider the implications of such cross-talk in vasodilator control in health and disease.
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- 2014
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31. Ceruloplasmin dysfunction: a key factor in the pathophysiology of atrial fibrillation?
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Jeremy JY and Shukla N
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- Humans, Male, Atrial Fibrillation blood, Ceruloplasmin genetics, Ceruloplasmin metabolism, Gene Frequency, Polymorphism, Single Nucleotide
- Published
- 2014
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32. Low nanomolar thapsigargin inhibits the replication of vascular smooth muscle cells through reversible endoplasmic reticular stress.
- Author
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Shukla N, Wan S, Angelini GD, and Jeremy JY
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- Dose-Response Relationship, Drug, Humans, Time Factors, Cell Division drug effects, Endoplasmic Reticulum Stress drug effects, Enzyme Inhibitors pharmacology, Muscle, Smooth, Vascular cytology, Thapsigargin pharmacology
- Abstract
Thapsigargin (TG), an inhibitor of Ca(2+) ATPase pumps in the endoplasmic reticulum (ER), inhibits replication of human vascular smooth muscle cell (hVSMC) at low nM concentrations. TG blocks replication of other cell types through promotion of ER stress (ERS). In order to determine whether ERS may mediate the cytostatic effect of TG in hVSMCs, the effect of TG on ERS in hVSMCs was studied by assessing markers of ERS: Immunoglobulin Heavy Chain Binding Protein (BiP), growth inhibitory transcription factor, GADD153, phosphorlylated eukaryotic initiation factor 2α (p-eIF2α) and phosphorlylated protein kinase R (p-PKR). hVSMCs derived from saphenous veins were rendered quiescent with serum-free medium for 96 h incubated with 10 nM TG at 37 °C for 24 h, then washed free of TG and incubated with 10% foetal calf serum (FCS) for a further 24 h. At selected times, BiP, GADD153, p-eIF2α, p-PKR and cyclin D1 expression was assessed. TG promoted a marked increase in BiP and GADD153, but suppressed cyclin D1 mRNA and protein expression. Under serum-free conditions p-eIF2α and p-PKR expression was not enhanced by TG. 15-24 h After removal of TG all these factors returned to levels seen in control cells. These data demonstrate that the inhibitory effect of 10nM TG on hVSMC replication is mediated through induction of ERS and associated factors that cessate replication and is reversible. These observations have implications in the aetiology and treatment of diseases that include atherogenesis, vein graft failure and restenosis., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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33. Role of osteopontin in the development of neointimal hyperplasia in vein grafts.
- Author
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Kang N, Ng CS, Hu J, Qiu ZB, Underwood MJ, Jeremy JY, and Wan S
- Subjects
- Anastomosis, Surgical methods, Animals, Carotid Arteries surgery, Cell Proliferation, Coronary Artery Bypass, Graft Rejection, Hyperplasia metabolism, Hyperplasia physiopathology, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Muscle, Smooth, Vascular pathology, Neointima metabolism, Osteopontin metabolism, Proliferating Cell Nuclear Antigen metabolism, Saphenous Vein metabolism, Saphenous Vein pathology, Sus scrofa, Tunica Intima pathology, Neointima pathology, Osteopontin physiology, Saphenous Vein transplantation
- Abstract
Objectives: Neointimal hyperplasia and superimposed atherosclerosis are central to late vein graft failure following coronary artery bypass grafting. Recent studies on post-injury arterial vessels have suggested a role of osteopontin (OPN) in the process of vascular remodelling. This study was designed to assess the in vivo performance of OPN following vein grafting., Methods: Bilateral saphenous vein-carotid artery interposition grafting was performed in 16 Large White pigs (35-45 kg). All patent vein grafts were removed and fixed at 1, 2, 4 (n = 8 grafts in each group) and 12 weeks (n = 6 grafts) following surgery. Multiple histological sections from each graft were prepared. The expression of OPN in the vein grafts was determined by immunostaining and western blot assay. Proliferating cell nuclear antigen (PCNA) was detected by immunocytochemistry. Vein graft morphology was assessed using computer-aided planimetry., Results: The expression of OPN remarkably increased in the intima of the vein grafts at the first week postoperatively and then gradually declined from the second postoperative week, although OPN expression remained significantly higher than the baseline level at the end of the 3-month study period. More importantly, the number of PCNA-positive cells and matrix metalloproteinases (MMPs) expression correlated well with the OPN expression., Conclusions: Early induction of OPN in vein grafts may contribute to the subsequent increase in MMPs activities as well as vascular smooth muscle cell proliferation. Therefore, OPN could play an important role in the development of neointimal hyperplasia in venous conduits after coronary artery bypass grafting.
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- 2012
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34. NADPH oxidase 4 mediates upregulation of type 4 phosphodiesterases in human endothelial cells.
- Author
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Muzaffar S, Jeremy JY, Angelini GD, and Shukla N
- Subjects
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid pharmacology, Alternative Splicing, Cyclic Nucleotide Phosphodiesterases, Type 4 genetics, Dinoprost analogs & derivatives, Dinoprost pharmacology, Enzyme Inhibitors metabolism, Gene Silencing, Human Umbilical Vein Endothelial Cells drug effects, Humans, Iloprost pharmacology, Isoenzymes genetics, Membrane Proteins genetics, Membrane Proteins metabolism, NADPH Oxidase 4, NADPH Oxidase 5, NADPH Oxidases genetics, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction physiology, Tumor Necrosis Factor-alpha pharmacology, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, Human Umbilical Vein Endothelial Cells enzymology, Isoenzymes metabolism, NADPH Oxidases metabolism, Up-Regulation
- Abstract
The protective actions of prostacyclin (PGI(2) ) are mediated by cyclic AMP (cAMP) which is reduced by type 4 phosphodiesterases (PDE4) which hydrolyze cAMP. Superoxide (O2(-)) from NADPH oxidase (Nox) is associated with impaired PGI(2) bioactivity. The objective of this study, therefore, was to study the relationship between Nox and PDE4 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with the thromboxane A(2) analog, U46619, 8-isoprostane F(2α) (8IP), or tumor necrosing factor alpha (TNFα) [±iloprost (a PGI(2) analog)] and the expression of PDE4A, B, C, and D and splice variants thereof assessed using Western blotting and qPCR and mRNA silencing of Nox4 and Nox5. Effects on cell replication and angiogenesis were also studied. U46619, 8IP, and TNFα increased the expression of Nox 4 and Nox 5 and all PDE4 isoforms as well as cell replication and tubule formation (index of angiogenesis), effects inhibited by mRNA silencing of Nox4 (but not Nox5) and iloprost and rolipram. These data demonstrate that upregulation of Nox4 leads to an upregulation of PDE4A, B, and D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis. This mechanism may be central to vasculopathies associated with endothelial dysfunction since the PGI(2)-cAMP signaling axis plays a key role in mediating functions that include hemostasis and angiogenesis., (Copyright © 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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35. Oxidative stress and vein graft failure: a focus on NADH oxidase, nitric oxide and eicosanoids.
- Author
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Weaver H, Shukla N, Ellinsworth D, and Jeremy JY
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- Animals, Eicosanoids metabolism, Enzyme Inhibitors therapeutic use, Humans, Multienzyme Complexes antagonists & inhibitors, NADH, NADPH Oxidoreductases antagonists & inhibitors, Neointima prevention & control, Nitric Oxide metabolism, Oxidative Stress, Thrombosis prevention & control, Coronary Artery Bypass adverse effects, Multienzyme Complexes metabolism, NADH, NADPH Oxidoreductases metabolism, Neointima metabolism, Thrombosis metabolism
- Abstract
Recent interest has focused on superoxide and the upregulation of NADPH oxidase expression in the aetiology of vein graft failure. Implantation of saphenous vein grafts promotes upregulation of NADPH oxidase through a number of distinct interrelated mechanisms: (a) endothelial denudation, (b) factors released by adherent platelets, monocytes and neutrophils, (c) hypoxia and (d) altered prostacyclin (PGI(2)) and enhanced isoprostane formation. These, in turn, impact on neointima (NI) formation (vascular smooth muscle cell [VSMC] replication and migration) and metalloproteinase (MMP) expression, key events in vein graft thickening. NADPH oxidase in the aetiology of vein graft failure will be discussed in this review with particular reference to nitric oxide and eicosanoids and related drugs that inhibit its activity and expression., (Copyright © 2012. Published by Elsevier Ltd.)
- Published
- 2012
- Full Text
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36. Pharmacological strategies aimed at reducing complications associated with coronary artery bypass graft surgery.
- Author
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Jeremy JY, Zacharowski K, Shukla N, and Wan S
- Subjects
- Angiotensin-Converting Enzyme Inhibitors therapeutic use, Antioxidants therapeutic use, Cell Movement drug effects, Cell Proliferation drug effects, Cytostatic Agents therapeutic use, Drug-Eluting Stents, Epoprostenol therapeutic use, Humans, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle physiology, Nitric Oxide Donors therapeutic use, Phosphodiesterase Inhibitors therapeutic use, Postoperative Complications prevention & control, Coronary Artery Bypass adverse effects, Saphenous Vein transplantation
- Published
- 2012
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37. Pathophysiology of saphenous vein graft failure: a brief overview of interventions.
- Author
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Shukla N and Jeremy JY
- Subjects
- Animals, Cytostatic Agents therapeutic use, Drug-Eluting Stents, Fibrinolytic Agents therapeutic use, Genetic Therapy, Graft Occlusion, Vascular physiopathology, Humans, Neointima physiopathology, Neointima prevention & control, Platelet Aggregation Inhibitors therapeutic use, Thrombosis physiopathology, Thrombosis prevention & control, Coronary Artery Bypass, Graft Occlusion, Vascular prevention & control, Saphenous Vein transplantation
- Abstract
Coronary artery bypass graft surgery (CABG) is widely used for the treatment of atheromatous stenosis of coronary arteries. However, as many as 50% of grafts fail within 10 years after CABG due to neointima (NI) formation, a process involving the proliferation of vascular smooth muscle cells (VSMCs) and superimposed atherogenesis. To date no therapeutic intervention has proved successful in treating late vein graft failure. However, several diverse approaches aimed at preventing neointimal formation have been devised which have yielded promising results. In this review, therefore, we will summarise the pathophysiology of vein graft disease and then briefly consider interventional approaches to prevent late vein graft failure which include surgical technique, conventional pharmacology, external sheaths, cytostatic drugs and gene transfer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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38. Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress.
- Author
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White SJ, Hayes EM, Lehoux S, Jeremy JY, Horrevoets AJ, and Newby AC
- Subjects
- Activating Transcription Factors metabolism, Binding Sites, Cells, Cultured, Cyclic AMP biosynthesis, Down-Regulation, Dual-Specificity Phosphatases biosynthesis, Endothelin-1 biosynthesis, Epoprostenol biosynthesis, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Profiling, Humans, Metallothionein biosynthesis, NADPH Oxidases biosynthesis, NF-E2-Related Factor 2 metabolism, Reactive Oxygen Species metabolism, Up-Regulation, Vasoactive Intestinal Peptide biosynthesis, Endothelial Cells physiology, Shear Strength, Stress, Mechanical
- Abstract
Most acute coronary events occur in the upstream region of stenotic atherosclerotic plaques that experience laminar shear stress (LSS) elevated above normal physiological levels. Many studies have described the atheroprotective effect on endothelial behavior of normal physiological LSS (approximately 15 dynes/cm(2)) compared to static or oscillatory shear stress (OSS), but it is unknown whether the levels of elevated shear stress imposed by a stenotic plaque would preserve, enhance or reverse this effect. Therefore we used transcriptomics and related functional analyses to compare human endothelial cells exposed to laminar shear stress of 15 (LSS15-normal) or 75 dynes/cm(2) (LSS75-elevated). LSS75 upregulated expression of 145 and downregulated expression of 158 genes more than twofold relative to LSS15. Modulation of the metallothioneins (MT1-G, -M, -X) and NADPH oxidase subunits (NOX2, NOX4, NOX5, and p67phox) accompanied suppression of reactive oxygen species production at LSS75. Shear induced changes in dual specificity phosphatases (DUSPs 1, 5, 8, and 16 increasing and DUSPs 6 and 23 decreasing) were observed as well as reduced ERK1/2 but increased p38 MAP kinase phosphorylation. Amongst vasoactive substances, endothelin-1 expression decreased whereas vasoactive intestinal peptide (VIP) and prostacyclin expression increased, despite which intracellular cAMP levels were reduced. Promoter analysis by rVISTA identified a significant over representation of ATF and Nrf2 transcription factor binding sites in genes upregulated by LSS75 compared to LSS15. In summary, LSS75 induced a specific change in behavior, modifying gene expression, reducing ROS levels, altering MAP kinase signaling and reducing cAMP levels, opening multiple avenues for future study., (Copyright © 2011 Wiley-Liss, Inc.)
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- 2011
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39. Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists.
- Author
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Jeremy JY, Shukla N, Angelini GD, and Wan S
- Subjects
- Endothelin-1 pharmacology, Endothelin-1 therapeutic use, Graft Occlusion, Vascular metabolism, Graft Occlusion, Vascular prevention & control, Graft Rejection metabolism, Graft Rejection prevention & control, Humans, Molecular Targeted Therapy, Neointima physiopathology, Receptor, Endothelin A physiology, Veins metabolism, Veins physiopathology, Endothelin A Receptor Antagonists, Endothelin-1 physiology, Graft Occlusion, Vascular drug therapy, Graft Rejection drug therapy, Veins drug effects
- Abstract
Despite the exploration of a large number of disparate drugs in animal models and clinical trials, no pharmacological intervention, with the exception of aggressive lipid lowering therapy has reduced late vein graft failure in man. The importance of devising more effective strategies is exemplified by the enormous economic consequences of vein graft failure. Worldwide, there are currently more than 1,000,000 coronary artery bypass graft surgery (CABG) operations a year, the same number of patients undergoing infrainguinal bypass for vascular diseases of the lower limb. The pathophysiology of vein graft failure is complex, involving disparate factors that include adhesion of platelets and leukocytes, rheological forces, metalloproteinase expression, proliferation and migration of vascular smooth muscle cells, neointima formation, oxidative stress, hypoxia and neural re-organisation. Although this diverse etiology may seem to preclude any single drug type as being effective in mediating vein graft failure: one factor that is involved in every facet of vein graft pathobiology is endothelin-1 (ET-1). As such a single drug type (ET(A) antagonist) may prove to be the magic bullet in this scenario. Thus, in this review, we will consider the etiology of vein graft disease in relation to ET-1 and will then present an argument (with evidence) that specific ET(A) receptor antagonists constitute a potentially effective means of preventing vein graft failure., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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40. NADPH oxidase 1 mediates upregulation of thromboxane A2 synthase in human vascular smooth muscle cells: inhibition with iloprost.
- Author
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Muzaffar S, Shukla N, Massey Y, Angelini GD, and Jeremy JY
- Subjects
- Acetophenones pharmacology, Gene Silencing, Humans, Muscle, Smooth, Vascular drug effects, NADH, NADPH Oxidoreductases antagonists & inhibitors, NADH, NADPH Oxidoreductases deficiency, NADH, NADPH Oxidoreductases genetics, NADPH Oxidase 1, RNA, Small Interfering genetics, Iloprost pharmacology, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, NADH, NADPH Oxidoreductases metabolism, Thromboxane-A Synthase genetics, Thromboxane-A Synthase metabolism, Up-Regulation drug effects
- Abstract
Thromboxane A(2) (TXA(2)) upregulates and activates NADPH oxidase (Nox) both of which are associated with cardiovascular disease. The aim of this study, therefore, was to investigate the relationship between thromboxane A(2) synthase (TXAS) status and Nox in human vascular smooth muscle cells (hVSMCs), in particular, whether superoxide (O(2)(▪-)) derived from Nox influences TXAS expression and activity. hVSMCs were incubated with TNFα: (10 ng/ml), TXA(2) mimetic U46619 (100 nM), 8-isoprostane F(2α) (8-IP; 100 nM) and hypoxia. Expression of TXAS was assessed using western blotting and quantitative PCR. The role of Nox1 and Nox4 was studied using apocynin and mRNA silencing. The effect of the thromboxane receptor antagonist picotamide and of iloprost, a prostacyclin (PGI(2)) analogue was also studied. TNF-α, U46619 and 8-IP and hypoxia all augmented TXAS expression as well as TXA(2) formation, effects inhibited by apocynin. Nox-1 (but not Nox4) gene silencing inhibited the increase in TXAS expression and activity. Both picotamide and iloprost inhibited the upregulation of TXAS as well as TXA(2) formation induced by TNF-α, U46619 and 8-isoprostane F(2α) and hypoxia. It is concluded that upregulation of TXA(2) synthase expression and activity in human VSMCs is mediated by an a priori upregulation of Nox1 and represents a self amplifying cascade. The inhibition of this effect with iloprost consolidates that PGI(2) plays a protective anti-oxidative role in the vasculature and that picotamide and like drugs may be effective in reducing the incidence of cardiovascular disease associated with an oxidative aetiology., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2011
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41. 8-isoprostane F2α up-regulates the expression of type 5 phosphodiesterase in cavernosal vascular smooth muscle cells: inhibition with sildenafil, iloprost, nitric oxide and picotamide.
- Author
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Hotston M, Jeremy JY, Persad R, Bloor J, and Shukla N
- Subjects
- Animals, Blotting, Western, Dinoprost metabolism, Dinoprost pharmacology, Enzyme-Linked Immunosorbent Assay, Iloprost pharmacology, Male, Muscle, Smooth, Vascular cytology, NADP metabolism, Nitric Oxide, Oxidative Stress drug effects, Penis drug effects, Phthalic Acids pharmacology, Piperazines pharmacology, Purines pharmacology, Rabbits, Sildenafil Citrate, Sulfones pharmacology, Superoxides metabolism, Up-Regulation, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, Dinoprost analogs & derivatives, Impotence, Vasculogenic etiology, Myocytes, Smooth Muscle metabolism, Penis metabolism, Phosphodiesterase 5 Inhibitors pharmacology
- Abstract
Objectives: To explore the possible role of of 8-isoprostane F(2α) (8-IPF(2α) ) in the aetiology of erectile dysfunction (ED), as the over-production of superoxide (O(2)(-)) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in the formation of 8-IPF(2α) in vascular tissue, which has similar properties to thromboxane A(2) (TXA(2) ). TXA(2) is vasoconstrictor and up-regulates the expression of NADPH oxidase and phosphodiesterase type 5 (PDE5)., Materials and Methods: Cavernosal vascular smooth muscle cells (CVSMCs) were incubated with 8-IPF(2α) or the TXA(2) analogue, U46619, ±sildenafil, iloprost (a stable prostacyclin [PGI(2) ] analogue) or the nitric oxide (NO) donor NONOate for 16 h. The formation of O(2)(-) was then measured, PDE5 expression assessed using Western blotting and PGI(2) and 8-IPF(2α) formation measured using enzyme-linked immunoassays., Results: 8-IPF(2α) promoted the formation of O(2)(-) , an effect inhibited by apocynin (an NADPH oxidase inhibitor) and up-regulated the expression of PDE5. Under identical incubation conditions, 8-IPF(2α) induced an increase in the formation of 8-IPF(2α) but reduced the formation of PGI(2) . All, these effects were reversed by sildenafil, iloprost, NONOate and picotamide., Conclusions: These data show that O(2) (-) derived from NADPH oxidase influences the relative balance of PGI(2) and 8-IPF(2α) in CVSMCs, which in turn alters the degree of PDE5 expression. This is a novel pathogenic mechanism underlying ED and a novel mechanism of action of sildenafil., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)
- Published
- 2010
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42. Folic acid administration reduces neointimal thickening, augments neo-vasa vasorum formation and reduces oxidative stress in saphenous vein grafts from pigs used as a model of diabetes.
- Author
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Bloor J, Shukla N, Smith FC, Angelini GD, and Jeremy JY
- Subjects
- Analysis of Variance, Animals, Blood Glucose, Carotid Arteries drug effects, Carotid Arteries pathology, Carotid Arteries surgery, Endothelium, Vascular drug effects, Endothelium, Vascular pathology, Saphenous Vein pathology, Statistics, Nonparametric, Swine, Tunica Intima pathology, Vasa Vasorum pathology, Vascular Patency drug effects, Diabetes Mellitus, Experimental pathology, Folic Acid administration & dosage, Oxidative Stress drug effects, Saphenous Vein drug effects, Saphenous Vein transplantation, Tunica Intima drug effects, Vasa Vasorum drug effects
- Abstract
Aims/hypothesis: There is evidence that plasma homocysteine augments vein graft failure and that it augments both micro- and macro-angiopathy in patients with diabetes mellitus. It is therefore suggested that homocysteine may augment vein graft thickening, a major cause of vein graft failure, in diabetic patients, as well as impairing adaptive growth of a new vasa vasorum, possibly through overproduction of superoxide. In order to test these proposals, the effect of folic acid administration, which lowers plasma homocysteine, on vein graft thickening and microvessel density was studied in pigs used as a model of diabetes., Methods: Non-ketotic hyperglycaemia was induced in Landrace pigs by intravenous injection of streptozotocin, and folic acid was fed daily for 1 month. Vein grafts were excised and the thickness of the neointima and media and microvessel density were assessed by planimetry and superoxide formation., Results: Plasma total homocysteine was significantly reduced by folic acid in both control and diabetic pigs, whereas glucose was unchanged. Compared with controls, diabetic pigs showed increased neointimal thickness and superoxide formation and decreased adventitial microvessel density. Folic acid reduced neointimal thickness and superoxide formation and augmented microvessel density in diabetic but not in control pigs., Conclusions: Folic acid administration reduces neointimal thickening, augments vasa vasorum neoformation and reduces oxidative stress in saphenous vein grafts from diabetic pigs. Folic acid may therefore be particularly effective in reducing vein graft failure in diabetic patients.
- Published
- 2010
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43. Animal models for studying neointima formation.
- Author
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Jeremy JY and Thomas AC
- Subjects
- Angioplasty, Balloon, Coronary adverse effects, Animals, Atherosclerosis etiology, Coronary Occlusion etiology, Disease Models, Animal, Dogs, Humans, Mice, Rabbits, Rats, Species Specificity, Swine, Thrombosis etiology, Treatment Failure, Angioplasty, Balloon adverse effects, Coronary Artery Bypass adverse effects, Tunica Intima pathology
- Abstract
Neointima (NI) formation following arterial bypass graft surgery or balloon angioplasty is considered central to subsequent failure after these procedures. The NI promotes accelerated atherogenesis, re-occlusion and thrombosis resulting in a failure rate as high as 50% within 1-10 years. Furthermore, despite the relative success of statins and drug eluting stents, drugs that reduce the failure rate have as yet not been implemented. In turn, animal models are a crucial means of testing potential interventions, in particular, drugs. The objective of this review therefore is to provide a survey of all the possible models that can be used to explore the effects of drugs on NI formation. The review will focus on the most commonly used of species, namely the rat, rabbit, mouse, pig and dog.
- Published
- 2010
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44. Saphenous vein harvest with the Mayo extraluminal dissector: is endothelial function preserved?
- Author
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Narayan P, Yeatman M, Caputo M, Capoun R, Ciulli F, Jeremy JY, and Angelini GD
- Subjects
- Aged, Aged, 80 and over, Coronary Artery Bypass, Cyclic GMP biosynthesis, Female, Humans, In Vitro Techniques, Male, Middle Aged, Saphenous Vein metabolism, Endothelium, Vascular metabolism, Saphenous Vein transplantation, Tissue and Organ Harvesting instrumentation
- Published
- 2009
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45. Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats.
- Author
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Shukla N, Rossoni G, Hotston M, Sparatore A, Del Soldato P, Tazzari V, Persad R, Angelini GD, and Jeremy JY
- Subjects
- Animals, Blotting, Western, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, Down-Regulation, Male, Muscle Relaxation drug effects, Myocytes, Smooth Muscle drug effects, Phosphodiesterase Inhibitors chemistry, Phosphodiesterase Inhibitors therapeutic use, Piperazines chemistry, Piperazines therapeutic use, Purines, Rabbits, Rats, Sildenafil Citrate, Sulfones chemistry, Sulfones therapeutic use, Erectile Dysfunction drug therapy, Oxidative Stress drug effects, Penile Erection drug effects, Phosphodiesterase Inhibitors pharmacology, Piperazines pharmacology, Sulfones pharmacology
- Abstract
OBJECTIVE To study the effect of the H(2)S-donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO). MATERIALS AND METHODS Relaxation was studied in an organ bath in response to carbachol and after incubation with interleukin-1beta for 12 h. CSMCs were incubated with tumour-necrosis factor-alpha or the thromboxane A(2) (TXA(2)) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47(phox) (an active subunit of the NADPH oxidase complex) and PDE5 protein was then assessed using Western blotting. Rats were also treated with BSO (with or with no sildenafil citrate or ACS6) for 7 days; cavernosal cGMP, cAMP, glutathionine and plasma TXA(2) and 8-isoprostane F(2alpha) was measured by enzyme-linked immunosorbent assay. RESULTS ACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 microm. The formation of superoxide and expression of p47(phox) and PDE5 was reduced by ACS6, sildenafil citrate and NaHS (order of potency: ACS6 > sildenafil citrate > NaHS). The effects of ACS6 were blocked by inhibitors of protein kinase A (PKA) and PKG. In rats treated with BSO, both ASC6 and sildenafil citrate reduced the increased plasma levels of TXA(2) and 8-isoprostane F(2alpha) but increased cGMP, cAMP and glutathionine levels in corpus cavernosum. CONCLUSIONS By virtue of a dual action on PKA and PKG activation, ACS6 not only promotes erection, acutely, but might also have a long-term beneficial effect through inhibition of oxidative stress and downregulation of PDE5.
- Published
- 2009
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46. The administration of folic acid improves erectile function and reduces intracavernosal oxidative stress in the diabetic rabbit.
- Author
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Shukla N, Hotston M, Persad R, Angelini GD, and Jeremy JY
- Subjects
- Animals, Antioxidants administration & dosage, Blotting, Western, Diabetes Mellitus, Experimental complications, Drug Evaluation, Preclinical, Erectile Dysfunction physiopathology, Folic Acid administration & dosage, Male, Oxidative Stress physiology, Penile Erection physiology, Rabbits, Treatment Outcome, Vasodilator Agents administration & dosage, Antioxidants pharmacology, Erectile Dysfunction drug therapy, Folic Acid pharmacology, Oxidative Stress drug effects, Penile Erection drug effects, Vasodilator Agents pharmacology
- Abstract
Objective: To test the possibility that folic acid (FA) may be a means of treating erectile dysfunction (ED) in diabetes mellitus (DM), by studying the effect of FA administration to DM rabbits on cavernosal function and intrapenile oxidative stress., Materials and Methods: To investigate the effect of administering FA to DM rabbits on erectile function and oxidative stress the formation of superoxide (O(2)(-)), 8-isoprostane F(2 alpha) (8-IPF(2 alpha)) and prostacyclin (as 6-keto-PGF(1 alpha)) were assessed, as well as carbachol- and electrical field stimulated (EFS) relaxation and p47(phox) content (active component of NADPH oxidase complex). Non-ketotic DM was induced in New Zealand rabbits with alloxan and FA administered orally daily for 1 month. Rabbits were killed, penises excised and segments prepared. These were mounted in an organ bath and relaxation elicited with carbachol or EFS. O(2)(-) release was measured spectrophotometrically, p47(phox) expression by Western blotting and 8-IPF(2 alpha) and 6-keto-PGF(1 alpha) formation by enzyme-linked immunosorbant assay. Blood was collected for measurement of homocysteine, red blood cell (RBC) folate and glucose., Results: In cavernosal tissue from DM rabbits, carbachol-and EFS-induced relaxation was significantly impaired compared with the untreated controls. O(2)(-) release, p47(phox) expression and 8-IPF(2 alpha) formation were all enhanced and 6-keto-PGF(1 alpha) formation reduced compared with the controls. All these effects were reversed by FA. Plasma total homocysteine was reduced and RBC folate elevated., Conclusions: The administration of FA may constitute a strategy for reducing ED in patients with DM.
- Published
- 2009
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47. H2S-donating sildenafil (ACS6) inhibits superoxide formation and gp91phox expression in arterial endothelial cells: role of protein kinases A and G.
- Author
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Muzaffar S, Jeremy JY, Sparatore A, Del Soldato P, Angelini GD, and Shukla N
- Subjects
- Adenylyl Cyclases metabolism, Animals, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases drug effects, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclic GMP metabolism, Cyclic GMP-Dependent Protein Kinases drug effects, Cyclic GMP-Dependent Protein Kinases metabolism, Endothelial Cells drug effects, Guanylate Cyclase metabolism, Inhibitory Concentration 50, Male, NADPH Oxidases drug effects, NADPH Oxidases metabolism, Phosphodiesterase 5 Inhibitors, Piperazines administration & dosage, Pulmonary Artery cytology, Respiratory Distress Syndrome drug therapy, Respiratory Distress Syndrome physiopathology, Sulfides administration & dosage, Sulfides pharmacology, Sulfones administration & dosage, Superoxides metabolism, Swine, Time Factors, Tumor Necrosis Factor-alpha pharmacology, Gene Expression Regulation drug effects, Hydrogen Sulfide metabolism, Piperazines pharmacology, Sulfones pharmacology, Superoxides antagonists & inhibitors
- Abstract
Background and Purpose: Superoxide (O(2)(*-)), derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, is associated with acute respiratory distress syndrome (ARDS). NADPH oxidase activity and expression are blocked by nitric oxide (NO) and sildenafil. As another gas, hydrogen sulphide (H(2)S) is formed by blood vessels, the effect of sodium hydrosulphide (NaHS) and the H(2)S-donating derivative of sildenafil, ACS6, on O(2)(*-) formation and the expression of gp91(phox) (a catalytic subunit of NADPH oxidase) in porcine pulmonary arterial endothelial cells (PAECs) was investigated., Experimental Approach: PAECs were incubated with 10 ng mL(-1) tumour necrosis factor-alpha (TNFalpha) (+/-NaHS or ACS6), both of which released H(2)S, for 2 h or 16 h. O(2)(*-) was measured. Expression of gp91(phox) was measured by western blotting and the role of cyclic AMP (cAMP) and/or cyclic GMP was assessed using protein kinase inhibitors., Key Results: After either 2- or 16-h incubations, O(2)(*-) formation by PAECs was inhibited by NaHS or ACS6, with IC(50) values of about 10 nM and less than 1 nM, respectively. Both 100 nM NaHS and 1 nM ACS6 completely inhibited gp91(phox) expression induced by TNFalpha. The effects of NaHS were blocked by the inhibition of protein kinase A (PKA), but not PKG, and not by the inhibition of guanylyl cyclase. Effects of ACS6 were blocked by inhibition of both PKA and PKG. Both NaHS and ACS6 augmented cAMP formation., Conclusion and Implications: H(2)S inhibited O(2)(*-) formation and upregulation of NADPH oxidase in PAECs through the adenylyl cyclase-PKA pathway. ACS6 may be effective in treating ARDS through both elevation of cAMP and inhibition of phosphodiesterase type 5 activity.
- Published
- 2008
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48. Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate.
- Author
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Muzaffar S, Shukla N, Bond M, Sala-Newby GB, Newby AC, Angelini GD, and Jeremy JY
- Subjects
- Cells, Cultured, Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism, Humans, Nitric Oxide Donors pharmacology, Saphenous Vein cytology, Superoxides pharmacology, Up-Regulation, Vasodilator Agents pharmacology, Iloprost pharmacology, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular enzymology, Muscle, Smooth, Vascular metabolism, NADPH Oxidases metabolism, Nitroso Compounds pharmacology, Phosphodiesterase 5 Inhibitors, Superoxides metabolism
- Abstract
Background and Purpose: To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs)., Experimental Approach: hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac(1) in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied., Key Results: Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity., Conclusions and Implications: These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO.
- Published
- 2008
- Full Text
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49. Homocysteine and copper interact to promote type 5 phosphodiesterase expression in rabbit cavernosal smooth muscle cells.
- Author
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Hotston M, Jeremy JY, Bloor J, Greaves NS, Persad R, Angelini G, and Shukla N
- Subjects
- Animals, Blotting, Western, Chelating Agents pharmacology, Data Interpretation, Statistical, Gene Expression Regulation, Enzymologic drug effects, In Vitro Techniques, Male, Myocytes, Smooth Muscle drug effects, NADPH Oxidases antagonists & inhibitors, Penicillamine pharmacology, Penis drug effects, Phosphodiesterase Inhibitors pharmacology, Piperazines pharmacology, Purines pharmacology, Rabbits, Reactive Oxygen Species metabolism, Sildenafil Citrate, Sulfones pharmacology, Copper pharmacology, Cyclic Nucleotide Phosphodiesterases, Type 5 biosynthesis, Homocysteine pharmacology, Myocytes, Smooth Muscle enzymology, Penis enzymology
- Abstract
Aim: To study the effects of homocysteine and copper on type 5 phosphodiesterase (PDE5) expression in cavernosal vascular smooth muscle cells (CVSMCs) and to investigate superoxide (O(2)(.-)) derived from nicotinamide adenine dinucleotide phosphate oxidase as homocysteine and copper generate O(2)(.-), and O(2)(.-) upregulates PDE5 expression., Methods: CVSMCs derived from rabbit penis were incubated with homocysteine or copper chloride with or without superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (nicotinamide adenine dinucleotide phosphate inhibitor) for 16 h. The expression of PDE5 and of glyceraldehyde-3-phosphate dehydrogenase (internal standard) was assessed using Western blot analysis. In parallel, O(2)(.-) was measured spectrophotometrically., Results: CuCl(2) alone (up to 10 micromol/L) and homocysteine alone (up to 100 micromol/L) had no effect on O(2)(.-) formation in CVSMCs compared to controls. In combination, however, homocysteine and CuCl(2) markedly increased O(2)(.-) formation, an effect blocked by SOD, catalase, apocynin, and sildenafil (1 micromol/L) when co-incubated over the same time course. PDE5 expression was also significantly increased in CVSMCs incubated with homocysteine and CuCl(2), compared to controls. This effect was also negated by 16-h co-incubation with SOD, catalase, apocynin and sildenafil., Conclusion: This represents a novel pathogenic mechanism underlying ED, and indicates that the therapeutic actions of prolonged sildenafil use are mediated in part through inhibition of this pathway., ((c) 2008, Asian Journal of Andrology, SIMM and SJTU. All rights reserved.)
- Published
- 2008
- Full Text
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50. The administration of folic acid reduces intravascular oxidative stress in diabetic rabbits.
- Author
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Shukla N, Angelini GD, and Jeremy JY
- Subjects
- Alloxan, Animals, Body Weight, Dinoprost analogs & derivatives, Dinoprost biosynthesis, Epoprostenol biosynthesis, Folic Acid therapeutic use, Homocysteine blood, Male, NADPH Oxidases physiology, Rabbits, Superoxides metabolism, Aorta metabolism, Diabetes Mellitus, Experimental metabolism, Folic Acid pharmacology, Oxidative Stress drug effects
- Abstract
There is evidence that plasma homocysteine augments angiopathy in patients with diabetes mellitus. Although lowering homocysteine with folic acid improves endothelial function, the precise mechanisms underlying this effect are unknown. To study this area further, the effect of administration of folic acid to diabetic rabbits on intraaortic oxidative stress was studied by assessing the formation of superoxide (O(2)(-)), 8-isoprostane F(2alpha) (8-IPF(2alpha)), and prostacyclin (as 6-keto-PGF(1alpha)) as well as acetylcholine-stimulated relaxation and gp47(phox) content. Nonketotic diabetes mellitus was induced in New Zealand rabbits with alloxan, and low- and high-dose folic acid was administered daily for 1 month. Rabbits were killed, aortae were excised, and rings were prepared. Rings were mounted in an organ bath, and relaxation was elicited with acetylcholine. The O(2)(-) release was measured spectrophotometrically; the gp47(phox) expression, by Western blotting; and the 8-IPF(2alpha) and 6-keto-PGF(1alpha) formation, by enzyme-linked immunosorbent assay. Blood was collected for measurement of homocysteine, red blood cell folate, and glucose. In aortae from the diabetic rabbits, acetylcholine-induced relaxation was significantly impaired compared with that in untreated controls. The O(2)(-) release, p47(phox) expression, and 8-IPF(2alpha) formation were all enhanced and 6-keto-PGF(1alpha) formation was reduced compared with controls. All these effects were reversed by both low- and high-dose folic acid. Plasma total homocysteine was reduced by high-dose, but not low-dose, folic acid. Red blood cell folate was elevated in both groups. The improvement of endothelial function in patients receiving folic acid may be due to inhibition of nicotinamide adenine nucleotide phosphate oxidase (NADPH) oxidase expression and therefore conservation of nitric oxide and prostacyclin bioavailability, 2 vasculoprotective factors.
- Published
- 2008
- Full Text
- View/download PDF
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