endothelin-1 and Graft-Occlusion--Vascular

The saphenous vein is the most commonly used bypass graft in patients with coronary artery disease. During routine coronary artery bypass, grafting the vascular damage inflicted on the vein is likely to stimulate the release of endothelin-1, a potent endothelium-derived vasoconstrictor that also possesses cell proliferation and inflammatory properties, conditions associated with vein graft failure. In both in vitro and in vivo studies, endothelin receptor antagonists reduce neointimal thickening. The mechanisms underlying these observations are multifactorial and include an effect on cell proliferation and cell/tissue damage. Much of the data supporting the beneficial action of endothelin-1 receptor antagonism at reducing intimal thickening and occlusion in experimental vein grafts were published over 20 years ago. The theme of the recent ET-16 conference in Kobe was "Visiting Old and Learning New". This short review article provides an overview of studies showing the potential of endothelin receptor antagonists to offer an adjuvant therapeutic approach for reducing saphenous vein graft failure and poses the question why this important area of research has not been translated from bench to bedside given the potential benefit for coronary artery bypass patients.

Topics: Animals; Cell Proliferation; Coronary Artery Bypass; Coronary Artery Disease; Disease Models, Animal; Drug Repositioning; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Graft Rejection; Humans; Saphenous Vein; Vascular Patency

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.

Topics: Endothelin A Receptor Antagonists; Endothelin-1; Graft Occlusion, Vascular; Graft Rejection; Humans; Molecular Targeted Therapy; Neointima; Receptor, Endothelin A; Veins

The saphenous vein is the most commonly used graft for revascularization procedures in patients with coronary artery disease and critical limb ischaemia. However, the patency rate of this vessel is poor, with a high proportion of patients requiring further surgery. Early graft occlusion is caused by vasoconstriction or thrombus formation, with later stages of graft failure being due to neointimal formation or atherosclerosis. Apart from its potent constrictor action, endothelin-1 is also a potent proliferative and proinflammatory peptide that is implicated in a number of vascular diseases. The surgical trauma caused during preparation of the saphenous vein as a bypass graft stimulates the release of a number of factors affecting vascular reactivity and structure, including endothelin-1. Endothelin-1 not only constricts animal and human isolated saphenous vein segments but also causes vascular smooth muscle proliferation and neointimal thickening in vitro, actions that are mediated via endothelin (A and B) receptors. Experimentally, the effects of subtype-selective and dual receptor antagonists have been shown to inhibit endothelin-1-mediated constriction and cell proliferation of the saphenous vein. In this review, data supporting a role of endothelin-1 in vein graft occlusion are presented, and the therapeutic potential of endothelin receptor antagonists in improving graft performance is discussed.

Topics: Animals; Coronary Artery Bypass; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Graft Occlusion, Vascular; Humans; Organ Culture Techniques; Receptors, Endothelin; Saphenous Vein

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 considerable 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 (IIBS) 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 aetiology may seem to preclude any single drug type as being effective in preventing vein graft failure, one factor that is involved in every facet of vein graft pathobiology is endothelin-1 (ET-1). Thus, in this review, we will consider the diverse aetiology of vein graft disease in relation to ET-1 and will then present an argument (with evidence) that ET-1(A) (ET(A)) receptor antagonists constitute a potentially effective means of preventing vein graft failure.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin-1; Graft Occlusion, Vascular; Hemodynamics; Humans; Muscle, Smooth, Vascular; Oxidative Stress; Veins

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Coronary Artery Disease; Coronary Vessels; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Graft Occlusion, Vascular; Humans; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Percutaneous Coronary Intervention; Polymorphism, Single Nucleotide; Postoperative Complications; Receptor, Endothelin A; Stents

Vein graft restenosis has an adverse impact on bridge vessel circulation and patient prognosis after coronary artery bypass grafting.. We used the extravascular supporter α-cyanoacrylate (α-CA), the local application rapamycin/sirolimus (RPM), and a combination of the two (α-CA-RPM) in rat models of autogenous vein graft to stimulate vein graft change. The aim of our study was to observe the effect of α-CA, RPM, and α-CA-RPM on vein hyperplasia.. Fifty healthy Sprague Dawley (SD) rats were randomized into the following 5 groups: sham, control, α-CA, RPM, and α-CA-RPM. Operating procedure as subsequently described was used to build models of grafted rat jugular vein on carotid artery on one side. The level of endothelin-1 (ET-1) was determined by enzyme-linked immunosorbent assay (ELISA). Grafted veins were observed via naked eye 4 weeks later; fresh veins were observed via microscope and image-processing software in hematoxylin-eosin (HE) staining and immunohistochemistry after having been fixed and stored" (i.e. First they were fixed and stored, and second they were observed); α-Smooth Muscle Actin (αSMA) and von Willebrand factor (vWF) were measured with reverse transcription-polymerase chain reaction (RT-PCR). Comparisons were made with single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant.. We found that intimal thickness of the α-CA, RPM, and α-CA-RPM groups was lower than that of the control group (p < 0.01), and the thickness of the α-CA-RPM group was notably lower than that of the α-CA and RPM groups (p < 0.05).. RPM combined with α-CA contributes to inhibiting intimal hyperplasia in rat models and is more effective for vascular patency than individual use of either α-CA or RPM.

Topics: Actins; Animals; Carotid Arteries; Cell Proliferation; Coronary Artery Bypass; Cyanoacrylates; Disease Models, Animal; Drug Combinations; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Male; Random Allocation; Rats, Sprague-Dawley; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; Time Factors; Treatment Outcome; Tunica Intima

Arteriovenous (AV) graft is frequently used as vascular access in hemodialysis patients. However, clotting or thrombosis of AV grafts often occurs and requires surgical removal. At present, the molecular pathogenesis underlying thrombosis of AV graft is not clear. The PTEN/Akt signaling has been implicated in the pathogenesis of vascular diseases. In this study, elevated PTEN expression and concomitant Akt inactivation was observed in endothelium of atherosclerotic brachial arteries from hemodialysis patients. To investigate whether PTEN upregulation affects endothelial function, adenovirus-mediated PTEN (Ad-PTEN) overexpression was performed in aorta rings and cultured endothelial cells. It was found that PTEN overexpression potently inhibited the microvessel sprouting in aorta rings and the angiogenic activities of endothelial cells including migration and tube formation. On the contrary, PTEN knockdown by RNA interference promoted the endothelial migration and reversed the Ad-PTEN-induced inhibition of endothelial migration. Expression analysis showed that PTEN overexpression attenuated the expression of endothelin-1 (ET-1) and endothelin B receptor (ETBR) in endothelial cells at transcriptional levels. However, exogenous ET-1 supply only partially reversed the PTEN-induced inhibition of migration and tube formation. This was delineated due to that PTEN overexpression also perturbed endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) release. In summary, PTEN upregulation induces endothelial dysfunction by attenuating the availability and signaling of multiple angiogenic pathways in endothelial cells, thereby may contribute to thrombosis of AV graft.

Topics: Animals; Arteriovenous Shunt, Surgical; Cell Movement; Endothelial Cells; Endothelin-1; Enzyme Activation; Graft Occlusion, Vascular; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Renal Dialysis; RNA Interference; Signal Transduction; Thrombosis; Tissue Culture Techniques; Transcription, Genetic; Transfection; Up-Regulation; Vascular Endothelial Growth Factor A

Inflammation is a major contributor to atherosclerotic vascular disease. Inflammatory parameters such as C-reactive protein (CRP) and Interleukin-6 (IL-6) have been shown to be strong predictors of cardiovascular events. The association between preoperative inflammatory parameters and early graft occlusion as well as cardiovascular events after coronary artery bypass grafting (CABG) has not, however, been fully elucidated. The aims of the present study were to prospectively investigate the prognostic value of the inflammatory parameters IL-6, CRP, and endothelin (ET-1) to predict early graft occlusion as well as late cardiovascular events after CABG.. In the present study 99 patients undergoing CABG because of stable angina pectoris due to significant coronary artery disease were prospectively included. Coronary angiography was repeated 3 months after CABG in 81 patients in order to evaluate early graft occlusion. Blood samples were collected before CABG in all patients. Patients were followed up for a median of 5 (3-7) years after CABG.. Twenty-five patients (31%) had one or more occluded grafts at the 3-month control coronary angiography. The patients with occluded grafts had higher preoperative CRP and IL-6 levels in plasma [CRP 2.22 (1.11-4.47) mg/L vs. 1.23 (0.71-2.27) mg/L P=0.03] and [IL-6 2.88 (1.91-5.94) pg/mL vs. 2.15 (1.54-3.14) pg/mL P=0.006]. There were 23 late cardiovascular events among the 99 patients during the follow-up. Patients experiencing late cardiovascular events had higher preoperative IL-6 levels than those without late cardiovascular events [4.13 (1.83-5.87) pg/mL vs. 2.08 (1.53-2.29) pg/mL, P=0.002] whereas CRP levels did not differ significantly between the two groups [1.5 (0.79-4.41) mg/L vs. 1.33 (0.74-2.48) mg/L, P=0.41]. Looking at IL-6, a cut off value more than 3.8 pg/ml was associated with a significant higher risk for an early graft occlusion (P=0.04) and late cardiovascular events (P=0.00003). Preoperative endothelin-1 did not predict early graft occlusions or late cardiovascular events.. Raised preoperative IL-6 levels are predictors of both early graft occlusion and late cardiovascular events after CABG. Elevated preoperative CRP levels can predict early graft occlusion after CABG. Endothelin did not differ between the two groups.

Topics: Aged; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Coronary Artery Bypass; Coronary Artery Disease; Endothelin-1; Female; Graft Occlusion, Vascular; Humans; Interleukin-6; Male; Middle Aged; Predictive Value of Tests; Time Factors; Treatment Outcome

Bypass graft stenosis after venous revascularisation procedures is characterised by massive neointimal and vascular smooth muscle cell proliferation triggered via endothelin-1 synthesis in the vessel wall. Decoy oligodesoxynucleotides (ODN) against the transcription factor activator protein-1 (AP-1) inhibits pre-pro-endothelin-1 expression.. In 20 rabbits, an end-to-side jugular vein bypass to the carotid artery was performed: (group A) 8 grafts were treated with consensus AP-1 decoy ODN, (group B) 8 with mutated control ODN and (group C) 4 received no treatment. Explantation, histomorphometric and immunohistochemical evaluation was performed after 28 days.. Median intimal thickness of groups: (A) 28.3 microm, (B) 48.4 microm, (C) 71.1 microm. The decoy ODN-treated group showed a significant reduction of neointima formation ( P = 0.029) and a downregulation of the endothelin receptor.. In this model, neointima formation was reduced by local transfection with consensus decoy ODN against AP-1. Endothelin A and B receptor expression is downregulated. Molecular target nucleic acid-based therapies seem to be a future means of overcoming neointima proliferation in pressure-induced venous graft failure. Intraoperative local application makes it easy to use in routine revascularisation procedures.

Topics: Animals; Carotid Arteries; Coronary Artery Bypass; Disease Models, Animal; Down-Regulation; Endothelin-1; Genetic Therapy; Graft Occlusion, Vascular; Male; Oligonucleotides; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Transcription Factor AP-1; Transfection; Tunica Intima

Topics: Coronary Artery Bypass; Coronary Artery Disease; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Muscle, Smooth, Vascular; Vasoconstriction

The saphenous vein (SV) is the most commonly used conduit for coronary artery bypass surgery. However, using traditional techniques, the occlusion rate for the SV is high, with over 50% of grafts failing within 10 years. In conventional coronary artery bypass surgery the SV is exposed to considerable damage during preparation for grafting. Recently, an increased graft patency has been described using a 'no-touch' technique, whereby the vein is prepared with minimal vascular trauma. There is evidence that the success of this form of coronary artery bypass surgery is a result, at least in part, of the retention of tissue-derived nitric oxide. We have examined the effects of conventional SV harvesting on vessel morphology, cell proliferation, endothelin-1 and its receptors. Considerable damage was observed in veins prepared using conventional surgery compared to 'no-touch' veins. The vessel wall exhibited evidence of surgical trauma, with regions of denudation of the luminal endothelium caused by distension. Endothelin-1 and endothelin-A receptors were present at subintimal regions of conventional SV segments where proliferating cells were identified. Endothelial endothelin-B receptors were also revealed that were absent at areas of distension-induced damage to the endothelium. These results suggest that endothelin-1 plays a role in vein graft failure, predominantly via the endothelin-A receptor.

Topics: Cell Proliferation; Coronary Artery Bypass; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Microscopy, Electron, Transmission; Receptor, Endothelin A; Receptor, Endothelin B; Saphenous Vein; Tissue and Organ Harvesting; Treatment Failure

Endothelin (ET)-1 levels were analyzed in patients who underwent elective coronary stenting. There was a significant increase in systemic ET-1 levels immediately after the procedure, which is probably a marker of endothelial dysfunction that is associated with arterial injury. However, there was no association between ET-1 levels and in-stent restenosis in humans.

Topics: Aged; Blood Vessel Prosthesis Implantation; Endothelin-1; Female; Graft Occlusion, Vascular; Humans; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Prospective Studies; Stents

Topics: Biopterins; Coronary Artery Bypass; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Insulin Resistance; Vascular Resistance

Thrombolytic therapy is frequently used to manage vascular graft thrombosis. However, long-term patency after thrombolysis remains poor. The purpose of this study was to characterise the morphological and functional response of endothelial cells (EC) exposed to a thrombus and subsequently lytic therapy.. Human EC were exposed to human whole blood thrombus for 2, 6, 12, and 24 h. The thrombus was lysed with urokinase. Cell morphology was studied with electron microscopy. Northern blot analyses were performed with human c-DNA probes for endothelin-1, thrombomodulin, tissue factor, tissue plasminogen activator, plasminogen activator inhibitor, and triose phosphate isomerase.. EC retraction occurred for each period of incubation. Thrombomodulin expression was increased 2.2-fold at 6 h and 2.4-fold at 24 h. t-PA expression was depressed proportionally to the duration of thrombus exposure. PAI and TF expression transiently increased 1.5-fold at 2 h of exposure and returned to baseline at 6 h. Endothelin expression remained unchanged.. Except for a transient increase in TF expression and reversal of the tPA/PAI ratio, EC exposed to thrombus do not appear to become actively procoagulant. The increase in TM expression may reflect enhanced thromboresistance. However, EC retraction may be responsible for an increase thrombogenicity of saphenous vein graft after thrombosis and Urokinase therapy.

Topics: Cells, Cultured; Endothelin-1; Endothelium, Vascular; Graft Occlusion, Vascular; Humans; Microscopy, Electron, Scanning; Plasminogen Activator Inhibitor 1; Saphenous Vein; Thrombolytic Therapy; Thrombomodulin; Thromboplastin; Thrombosis; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator