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Biomedical subjects

Jamie Y Jeremy

Publications and source records attributed to Jamie Y Jeremy.

33 records · Page 2Linked to original sources
PubMed2004

Nitroaspirins and morpholinosydnonimine but not aspirin inhibit the formation of superoxide and the expression of gp91phox induced by endotoxin and cytokines in pig pulmonary artery vascular smooth muscle cells and endothelial cells.

BACKGROUND: Although nonsteroidal antiinflammatory drugs (NSAIDs) are ineffective in treating acute respiratory distress syndrome (ARDS), inhalational NO has proved to be useful. NO-donating NSAIDs may therefore be more effective in treating ARDS than NSAIDs alone. Because oxidant stress is central to the pathophysiology of ARDS, the effect of nitroaspirins (NCX 4016, NCX 4040, and NCX 4050) compared with morpholinosydnonimine (SIN-1; an NO donor) and aspirin (ASA) on superoxide (O2*-) formation and gp91phox (an active catalytic subunit of NADPH oxidase) expression in pig pulmonary artery vascular smooth muscle cells (PAVSMCs) and endothelial cells (PAECs) was investigated. METHODS AND RESULTS: Cultured PAVSMCs and PAECs were incubated with lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1alpha (with or without NO-ASA, SIN-1, or ASA) for 16 hours, and O2*- release was measured by use of the reduction of ferricytochrome c. The expression of gp91(phox) was assessed by use of Western blotting. LPS, TNF-alpha, and IL-1alpha all stimulated the formation of O2*- and expression of gp91(phox) in both PAVSMCs and PAECs, an effect inhibited by NADPH oxidase inhibitors, diphenyleneiodonium, and apocynin. SIN-1, NCX 4016, and NCX 4050 but not ASA alone inhibited the formation of O2*- and expression of gp91(phox). CONCLUSIONS: LPS and cytokines promote the formation of O2*- in PAVSMCs and PAECs through an augmentation of NADPH oxidase activity, which in turn is prevented by NO. Thus, NO may play a protective role in preventing excess O2*- formation, but its negation by O2*- may augment the progress of ARDS. The inhibitory effect of nitroaspirins suggests that they may be therapeutically useful in treating ARDS through the suppression of NADPH oxidase upregulation and O2*- formation.

Acetophenones↗
PubMed2004

Iloprost inhibits superoxide formation and gp91phox expression induced by the thromboxane A2 analogue U46619, 8-isoprostane F2alpha, prostaglandin F2alpha, cytokines and endotoxin in the pig pulmonary artery.

Since the roles of thromboxane A2 (TXA2), prostacyclin (PGI2) and 8-isoprostane F2alpha in mediating vascular O2*- formation and its relation to adult respiratory distress syndrome (ARDS) is unknown, the effects of these eicosanoids on the expression of gp91phox (catalytic subunit of NADPH oxidase) and O2*- release from cultured pig pulmonary artery (PA) segments, PA vascular smooth muscle cells (PAVSMCs) and PA endothelial cells (PAECs) were investigated. PA segments, PAVSMCs and PAECs were incubated with the TXA2 analogue, U46619, (+/-LPS, tumour necrosing factor-alpha (TNF-alpha) or IL-1alpha), 8-isoprostane F2alpha and+/-iloprost (a stable PGI2 analogue) for 16 h. The formation of superoxide dismutase-inhibitable O2*- was then measured spectrophotometrically and gp91phox expression assessed using Western blotting. In parallel experiments, whole PA segments were treated with LPS, TNF-alpha and IL-alpha after which time TXA2, PGI2, PGF2alpha and 8-isoprostane F2alpha formation was measured using enzyme-linked immunoassays. U46619, PGF2alpha and 8-isoprostane F2alpha promoted the formation of O2*- in PA segments, PAVSMCs and PAECs, an effect inhibited by diphenyleneiodonium and apocynin (both NADPH oxidase inhibitors) and upregulated the expression of gp91phox in PAECs and PAVSMCs. These effects were augmented by LPS, TNF-alpha and IL-1alpha but inhibited by iloprost. Under identical incubation conditions, IL-1alpha, LPS and TNF-alpha all induced an increase in the formation of TXA2, PGF2alpha and 8-isoprostane F2alpha but reduced the concomitant formation of PGI2. These data demonstrate that LPS and cytokines influence the relative balance of TXA2, PGI2, PGF2alpha and 8-isoprostane F2alpha in pig PA, which in turn alter NADPH oxidase expression and O2*- formation. These novel findings have implications in devising effective strategies for treating ARDS.British Journal of Pharmacology (2004) 141, 488-496. doi:10.1038/sj.bjp.0705626

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts.

OBJECTIVE: Late saphenous vein graft failure after coronary artery bypass graft surgery is initiated by medial thickening and neointima formation, both of which are mediated by the proliferation of vascular smooth muscle cells. Because porcine vein grafts contain high levels of endothelin 1 receptor subtypes and endothelin 1 promotes the proliferation of vascular smooth muscle cells, the effect of administration of the endothelin 1(A) receptor antagonist BSF 302146 ([+]-[S]-2-[4,6-dimethyl-pyrimidin-2-yloxy]-3,3-diphenyl-butanoic acid) on porcine vein graft thickening was investigated. METHODS: Saphenous vein-carotid artery interposition grafting was performed in 4 groups of large white pigs (30-35 kg, n = 10 for each group). BSF 302146 was administered orally (3, 10, and 30 mg x kg(-1) x d(-1)) for 4 weeks to one group of pigs, and placebo was administered to the other group (control animals). Pigs were then anesthetized, and the grafts were removed and fixed at 100 mm Hg with 4% paraformaldehyde. Histologic sections were prepared, and graft morphometry was carried out by using computer-aided planimetry. RESULTS: In vein grafts from animals treated with BSF 302146 compared with grafts from control animals (untreated), there were significant dose-dependent reductions in the increase in medial thickness and neointimal thickness, an increase in luminal area, and a decrease in proliferating cell nuclear antigen-positive cells in the medial-intimal area. CONCLUSIONS: The administration of BSF 302146 reduces graft thickening and promotes positive remodeling through an endothelin 1(A)-mediated effect on vascular smooth muscle cell replication. The administration of this endothelin 1(A) receptor antagonist might therefore be therapeutically effective in preventing late vein graft failure in patients undergoing coronary artery bypass grafting.

Administration, Oral↗
PubMed2004

A bioabsorbable (polyglactin), nonrestrictive, external sheath inhibits porcine saphenous vein graft thickening.

OBJECTIVE: External, nonrestrictive, macro-porous polyester stents prevent neointima formation in porcine vein grafts and have been proposed as a therapeutic approach to the prevention of late vein graft failure. These stents are nonbiodegradable and therefore may promote long-term foreign body problems including infection and inflammation. The effect of external macro-porous biodegradable (polyglactin) sheaths on neointimal and medial thickening in porcine vein grafts was therefore investigated. METHODS: Bilateral saphenous vein-carotid artery interposition grafting was performed in white Landrace pigs (n = 8) with external placement of polyglactin (Vicryl) sheaths (8 mm in diameter) on 1 side, with the contralateral side acting as a control. One month after surgery, grafts were explanted and wall dimensions measured on histological sections using computer-aided planimetry, and an immunocytochemical appraisal was carried out. RESULTS: All grafts were patent at explantation. Polyglactin sheaths significantly reduced intimal thickness, medial thickness, and the percentage of proliferating cells compared with unsheathed controls. There was a pronounced accumulation of macrophages, giant cells, endothelial cells, and microvessels within and surrounding the biodegradable sheath compared with controls. CONCLUSIONS: A nonrestrictive, biodegradable (polyglactin), external sheath reduces medial and intimal thickening in experimental saphenous vein grafts, possibly through inflammatory cell-mediated angiogenesis. If subsequent long-term studies confirm preservation of this beneficial effect, once the sheath biodegrades, this approach may have an advantage over the permanent polyester stent when applied clinically.

Analysis of Variance↗
PubMed2004

Long-term reduction of medial and intimal thickening in porcine saphenous vein grafts with a polyglactin biodegradable external sheath.

OBJECTIVES: The development of neointimal hyperplasia with subsequent atherosclerotic deposition has been proposed to cause most late vein graft failures. Our unit has previously demonstrated that placement of a macroporous, loose-fitting polyester external stent prevents neointimal thickening in porcine vein grafts, and has been proposed as a therapeutic strategy to prevent late vein graft failure. To reduce any potential long-term complications of the permanent polyester stent, a study was undertaken to investigate the effect of a biodegradable external stent on porcine vein graft thickening at 1 month and to identify its longer term effects at 6 months. METHODS: Bilateral saphenous vein to common carotid artery interposition grafting was performed in Large White pigs (25-32 kg; n = 6 per time course group) according to UK Home Office guidelines. A commercially constructed loose-fitting 8-mm-diameter polyglactin stent was placed externally around the vein graft on one side, and the contralateral side remained unstented to serve as control. The external stent was designed to biodegrade and hence disappear within 90 days. Grafts were left in situ for 1 month in 1 group of animals, and for up to 6 months in the other group, before explantation. Graft morphometric features were assessed with computer-aided planimetry. RESULTS: At 1 month the vein grafts fitted with the polyglactin stent demonstrated a statistically significant decrease in neointimal thickening (0.038 mm; interquartile range [IQR], 0.035-0.039 mm) compared with the unstented control grafts (0.13 mm; IQR; 0.11-0.19; P = .0012), and also in medial thickening (0.09 mm; IQR, 0.086-0.093) compared with unsheathed control grafts (0.302 mm; IQR, 0.272-0.414; P = .0012). The 6-month polyglactin stented grafts also demonstrated a statistically significant reduction in neointimal thickening (0.049 mm; IQR, 0.047-0.07; P = .0012) compared with control grafts (0.178 mm; IQR, 0.164-0.19), and also in medial thickening (0.105 mm; IQR, 0.095-0.143) compared with unstented grafts (0.421 mm; IQR, 0.35-0.44; P = .0012, Mann-Whitney U test). CONCLUSION: The loose-fitting biodegradable polyglactin external stent reduces porcine vein graft thickening at 1 month, which persists in the long term, even after degradation of the stent itself. This effective removal of the stent may therefore reduce the long-term risks for infection and mechanical complications associated with implanted prosthetic material while still eliciting the primary objective of preventing graft thickening over the long term. Biodegradable external stents therefore have potential advantages over permanent stent material in clinical application. CLINICAL RELEVANCE: Arteriovenous bypass graft failure has a huge economic effect on health care resources, and a devastating effect o the patient. The attenuation of vein wall thickening, with subsequent luminal narrowing and occlusion, is a major goal in improving the longevity of the venous graft, to reduce secondary percutaneous and surgical interventions. The biodegradable external stent demonstrated in this study has possible clinical applications in bypass procedures with autogenous venous tissue, and represents a novel approach to ameliorating the problem of intimal hyperplasia that plagues these grafts.

Animals↗
PubMed2004

Moderately elevated plasma homocysteine impairs functional endothelial recovery following denudation of mouse carotid arteries.

Increased total plasma homocysteine is an independent risk factor for cardiovascular disease. This study was designed to determine whether it can impair endothelial function, by examining the recovery of acetylcholine-evoked relaxation following mechanical denudation of the endothelium in the arteries of cystathionine beta-synthase knockout (CbetaS(+/-)) mice. Heterozygous CbetaS(+/-) mice had total plasma homocysteine concentrations significantly higher (8.9 +/- 1.1 micromol/L, n = 12) than strain-matched wild-types (4.6 +/- 0.4 micromol/L, n = 5; P =.003). Left common carotid arteries were denuded of endothelium using a 250-microm polytetrafluoroethylene filament. After 10 days, when the endothelium had completely regrown, relaxation to acetylcholine was measured in precontracted segments of artery. Uninjured right carotid arteries from the same animals served as internal controls. Relaxation to acetylcholine was significantly attenuated in the injured arteries of the CbetaS(+/-) mice, compared to wild-types (P =.017); furthermore, there was a significant negative correlation between sensitivity to acetylcholine and total plasma homocysteine concentration measured in the same animal (r = -0.69, P <.003). These data suggest that even modest homocysteinemia has a deleterious effect on the function of healed endothelium in mouse arteries. This may account for its adverse influence on chronic cardiovascular disease.

Acetylcholine↗
PubMed2004

Reactive oxygen species, vascular disease and cardiovascular surgery.

Oxidant stress [ OS ] is a condition in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen called reactive oxygen species [ROS], principal amongst which is superoxide [O2-]. It is becoming increasingly apparent that O2- is a key risk factor for cardiovascular disease [CVD], including atherogenesis, reperfusion injury, angina, restenosis following balloon angioplasty and vein graft failure. When one considers the multiplicity of effects of O2-, this is perhaps not surprising, as it promotes vascular smooth muscle cell proliferation, damages the endothelium, promotes lipid oxidation and activates blood cells. However, perhaps the key reaction of O2- is that with nitric oxide [NO] to form peroxynitrite [ONOO] resulting in a depletion of endogenous vascular NO. Reduced NO formation is also now firmly associated with the aetiology of CVD and as such NO donors may become a major class of drugs. Furthermore, risk factors for CVD, in particular diabetes mellitus [DM], dyslipidaemia, and hyperhomocysteinaemia are all associated with OS. As such, it is becoming increasingly apparent that novel antioxidant therapies, including the gene transfer of antioxidant enzymes, are potentially valuable in the treatment of CVD. In this review, the aetiology of OS and CVD is discussed with particular emphasis on NO. The interactions of risk factors and how this pathophysiology relates to the design of effective novel strategies to treat CVD is also considered. Particular emphasis is also placed on OS and cardiovascular surgery.

Animals↗
PubMed2003

Delayed recovery of receptor-mediated functional responses to acetylcholine in mouse isolated carotid arteries following endothelial denudation in vivo.

The time-course of endothelial regrowth and functional recovery following polytetrafluoroethylene filament-induced endothelial denudation in vivo was studied in the left common carotid artery of the mouse. This technique does not result in any intimal hyperplasia, enabling the investigation of endothelial function without any confounding effect of intimal thickening. Endothelial coverage was assessed histologically, and functional recovery was assessed as restoration of receptor-mediated, endothelium-dependent relaxation to acetylcholine in vitro. Re-endothelialization of the carotid artery was complete within 8 days of denudation. However, relaxations to acetylcholine, which are mediated by endothelium-derived nitric oxide, were only partially restored 10 days after the procedure. At this time point, arterial responses to either phenylephrine, the receptor-independent endothelium-dependent dilator cyclopiazonic acid, or the nitric oxide donor diethylamine NONOate, were not significantly different to controls. At 25 days after denudation, acetylcholine-evoked responses remained significantly depressed compared to controls but at 90 days full recovery was observed. These data indicate that following mechanical denudation of the mouse carotid artery, although endothelial re-growth is complete within 8 days, recovery of endothelial cell function - assessed as the ability of the regenerated endothelium to mediate acetylcholine-stimulated relaxation - remains impaired for a prolonged period.

Acetylcholine↗
PubMed2003

Nitric oxide donating aspirins: novel drugs for the treatment of saphenous vein graft failure.

BACKGROUND: A new class of nitric oxide donating aspirin (NO-ASA) drugs may increase the therapeutic impact of aspirin in saphenous vein coronary artery bypass grafting (CABG) not only through the inhibition of thrombosis but also through a reduction of vasospasm and inhibition of vascular smooth muscle cell (VSMC) proliferation (effects that are inhibited by NO but not ASA). In order to test this proposal the effect of three NO-ASA drugs (NCX4040, NCX4050, and NCX4060) on in vitro relaxation and cyclic guanosine monophosphate (cGMP) formation in the human isolated saphenous vein and the proliferation of human VSMCs was investigated. METHODS: Saphenous vein segments were obtained from 30 patients undergoing CABG (median age, 59 years; range, 49 to 68). The effect of the NO-ASA adducts, ASA alone, and sodium nitroprusside (NO donor) were investigated on (1) relaxation of phenylephrine-stimulated contraction using an organ bath, (2) cyclic guanosine monophosphate (cGMP) formation using an enzyme-linked immunosorbent assay, and (3) the proliferation of VSMCs derived from saphenous vein using bromo-deoxyuridine (BRDU) incorporation. RESULTS: All three NO-ASA adducts (at concentrations that inhibited responses by 50% [IC50s] between 1 micromol/L and 100 micromol/L) and nitroprusside (at IC50s between 0.5 and 10 micromol/L) elicited relaxation of isolated human saphenous vein, promoted cGMP formation, and inhibited VSMC proliferation whereas ASA alone (up to 100 micromol/L) had no effect on any variable. CONCLUSIONS: These data indicate that the NO-ASA adducts by virtue of their capacity to release NO and stimulate guanylyl cyclase may be useful not only in the prevention of thrombosis following CABG but also the reduction of saphenous vein graft spasm and neointima formation.

Aged↗
PubMed2002

Sustained increases of plasma homocysteine, copper, and serum ceruloplasmin after coronary artery bypass grafting.

BACKGROUND: Homocysteine (Hcy) is an independent risk factor for coronary artery disease, but there are no reports on Hcy levels in patients undergoing coronary artery bypass graft (CABG) surgery. Interactions between Hcy and copper may mediate the vasculopathic impact of Hcy, and this may play a role in vein graft failure. The aim of this study was to assess the perioperative levels of Hcy, copper, ceruloplasmin (CP), folate, and vitamin B12 in patients undergoing myocardial revascularization surgery. METHODS: Blood samples were taken from 55 consecutive patients undergoing elective conventional CABG (43 male; mean age, 63.2 +/- 5.2 years) 1 day preoperatively and postoperatively at 1 day, 6 days, and 6 weeks. Hcy, copper, CP, red cell folate, vitamin B12, creatinine, and C-reactive protein (CRP) were then measured using standard clinical chemistry methods. The same protocol was applied to 10 patients (7 male; mean age, 63.3 +/- 5.2 years) undergoing off-pump coronary artery bypass (OPCAB) surgery. RESULTS: In the conventional CABG group, there were significant increases in the plasma concentrations at 6 days and 6 weeks postoperatively of Hcy (from 10.1 to 11.6 and 13.5 micromol/L, respectively), plasma copper (from 13.5 to 20.3 and 18.5 micromol/L), and serum ceruloplasmin (from 0.3 to 0.41 and 0.44 g/L). CRP and vitamin B12 were elevated at 6 days but not 6 weeks after the operation. In contrast, red cell folate and creatinine were not significantly changed. The subgroup analysis for the OPCAB patients showed the same trend as for the conventional group. CONCLUSIONS: Coronary surgery precipitates a significant and sustained increase in the blood concentrations of Hcy and copper, which is not due to a decrease in folate and vitamin B12, altered renal function, or inflammation. Further studies are required to establish whether the concomitant increase in Hcy and copper plays an etiological role in vein graft disease.

Aged↗
PubMed2002

Towards the treatment of saphenous vein bypass graft failure--a perspective of the Bristol Heart Institute.

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 and migration of vascular smooth muscle cells (VSMCs). Superimposed on neointima formation is accelerated atherogenesis which ultimately results in late vein graft failure. To date no therapeutic intervention has proved successful in treating late vein graft failure and as such is a matter of some urgency. However, in recent years, several diverse approaches aimed at preventing neointimal formation have been devised which have yielded promising results. These include the use of external stents, gene therapy as well as conventional pharmacological interventions. The objective of this article, therefore, is to review these recent approaches and their potential clinical applications in the treatment of vein graft disease.

Animals↗
PubMedDate not supplied

Oxidative stress, nitric oxide, and vascular disease.

Superoxide (O2-) is a key risk factor for cardiovascular disease (CVD), including atherogenesis, reperfusion injury, angina, restenosis following balloon angioplasty, and vein graft failure. Axiomatically, O2- reacts with nitric oxide (NO) to form peroxynitrite (ONOO) resulting in a depletion of endogenous vascular NO, which is now firmly associated with CVD. Furthermore, risk factors for CVD, in particular diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are all associated with oxidative stress OS. Antioxidant therapies, including the gene transfer of antioxidant enzymes, are potentially valuable in the treatment of CVD.

Apoptosis↗