endothelin-1 and Coronary-Restenosis

The prevalence of type 2 diabetes globally is reaching epidemic proportions. Type 2 diabetes is strongly associated with increased risk of cardiovascular disease. Atherosclerosis is thought to arise as a result of a chronic inflammatory process within the arterial wall. Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherogenesis, either directly or through associated risk factors. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, pioglitazone and rosiglitazone, are insulin sensitizing agents, that are licensed for the management of hyperglycaemia. Growing evidence supports an array of additional effects of thiazolidinedione therapy, both immunomodulatory and antiinflammatory, which may attenuate atherogenesis in type 2 diabetes.. Studies have shown that thiazolidinedione therapy may lead to risk factor modulation in type 2 diabetes. Thiazolidinediones treatment has been shown to reduce blood pressure, modify the atherogenic lipid profile associated with type 2 diabetes, reduce microalbuminuria and ameliorate the prothrombotic diathesis. Further evidence suggests that thiazolidinediones therapy inhibits the inflammatory processes which may be involved in atherosclerotic plaque initiation, propagation and destabilization.. Modification of insulin resistance by thiazolidinedione therapy in type 2 diabetes and the range of pleiotropic effects may not only impact on incident type 2 diabetes, but also on associated cardiovascular disease. Numerous large clinical endpoint studies are under way to investigate these issues.

Topics: Albuminuria; Arteriosclerosis; Blood Pressure; C-Reactive Protein; Carotid Arteries; Coronary Restenosis; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Humans; Hyperglycemia; Insulin Resistance; Lipoproteins; Matrix Metalloproteinases; Metformin; Muscle, Smooth, Vascular; Pioglitazone; Plasminogen Activator Inhibitor 1; PPAR gamma; Rosiglitazone; Thiazolidinediones

We compared the expression of signal molecules in the culture of human endothelial cells under normal conditions and in atherosclerosis and restenosis. Expression of connexin-37 and sirtuin-1 in atherosclerosis and restenosis surpassed the normal by 2 and 5 times, respectively, and expression of endothelin-1 3-fold surpassed the normal. In restenosis, changes in the expression connexin-37 and endothelin-1 became more pronounced in comparison with atherosclerosis. Connexin-37 and endothelin-1 can serve as predictive markers for prognosis of post-stenting complications in patients with atherosclerosis.

Topics: Atherosclerosis; Cells, Cultured; Connexins; Coronary Restenosis; Endothelial Cells; Endothelin-1; Humans

This study was designed to investigate the relation between plasma von Willebrand factor (VWF) or endothelin-1 (ET-1) and post-carotid artery stenting (CAS) restenosis.. Plasma levels of VWF and ET-1 were measured in 61 patients (36 males, mean age 64.4 ± 6.8 years) before and after CAS. The mean follow-up time was 13.8 ± 1.7 months (range, 6-63). In-stent restenosis was defined as a >10% narrowing of the vascular lumen with or without ischemic symptoms following CAS.. In-stent restenosis was identified in 14 (23%) patients, including 3 with >50% restenosis. In the restenosis group, mean VWF and ET-1 levels at 2 weeks, 1 and 6 months after CAS were higher than the baseline levels (p < 0.05 or p < 0.01). Mean levels of VWF and ET-1 in the restenosis group were higher than in the non-restenosis group within 6 months after CAS (p < 0.05 or p < 0.01).. Persistent elevation in plasma VWF and ET-1 within the first 6 months of CAS was found in patients with in-stent restenosis.

Topics: Aged; Analysis of Variance; Biomarkers, Pharmacological; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Endothelin-1; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Risk Assessment; Stroke; von Willebrand Factor

The relationship between vasoactive substances, including endothelin-1, nitric oxide, serotonin, angiotensin II and noradrenaline, and coronary restenosis after percutaneous transluminal coronary angioplasty (PTCA) is not clear.. To determine whether any vasoactive substance may be a marker of coronary restenosis after PTCA.. Twenty-nine patients with angina pectoris underwent elective PTCA. Three months after PTCA, coronary angiography was performed again to study the patency of the lesions. Seven patients had coronary restenosis (greater than 50% stenosis) (restenosis group) and the rest of the patients were without restenosis (patency group). Their blood samples were obtained from the coronary sinus before, immediately after and three months after PTCA.. Endothelin-1 levels obtained immediately after PTCA (3.44+/-0.26 pg/mL) and three months after PTCA (3.57+/-0.29 pg/mL) were significantly higher than those obtained before PTCA (3.00+/-0.26 pg/mL) in the restenosis group, but not in the patency group (3.34+/-0.15 pg/mL, 3.02+/-0.17 pg/mL and 3.14+/-0.18 pg/mL, respectively). A transient decrease in nitrite/nitrate levels was observed immediately after PTCA in both groups. The serotonin levels three months after PTCA were significantly decreased in the patency group, but not in the restenosis group, and the levels of angiotensin II and noradrenaline did not change in either group throughout the study.. Among several vasoactive substances, endothelin-1 seems to be associated with the process of coronary restenosis after PTCA. Increased endothelin-1 levels in the coronary circulation after PTCA may indicate an increased risk of coronary restenosis.

Topics: Aged; Angioplasty, Balloon, Coronary; Angiotensin II; Biomarkers; Coronary Angiography; Coronary Circulation; Coronary Restenosis; Endothelin-1; Female; Hemodynamics; Humans; Male; Middle Aged; Nitric Oxide; Norepinephrine; Risk Factors; Serotonin; Statistics as Topic; Vascular Patency

To investigate the effects of several vasoactive peptides on the development of arterial restenosis after balloon angioplasty.. In rat aortic artery restenosis model produced by denudation of aortic endothelia, we observed changes of endothelin (ET), angiotensin II (AII), calcitonin gene-related peptide (CGRP) and adrenomedullin (Adm) in plasma and aorta with radioimmunoassay and expression of hypertension-related gene (HRG-1) with semi-quantitative RT-PCR, and studied the effects of these peptides on intimal hyperplasia, intima/media ratio and MAPK activities of aortic artery after angioplasty respectively. Furthermore, in cultured cells, we studied the effects of these peptides on vascular smooth muscle cell (VSMC) proliferation and expression of HRG-1 of VSMC from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with 3H-TdR incorporation and RT-PCR respectively.. After angioplasty, the levels of ET and AII in plasma and aorta significantly increased, accompanied with VSMC proliferation and neointima hyperplasia. On day 10 after angioplasty, the levels of ET in plasma and aorta increased by 69% and 124% respectively, compared with sham group (P < 0.01); and the level of aortic AII increased by 80% (P < 0.01). Antiserum against ET or inhibitors of angiotensin converting enzyme (ACE) could significantly inhibit the proliferation of VSMC and neointima formation. Compared with the sham group, on day 3 after angioplasty, the CGRP levels in plasma and aorta increased by 64% and 89% respectively (P < 0.01) and the Adm levels in plasma and tissue increased by 129% and 102% respectively (P < 0.01). On day 10, intravenous administration of CGRP significantly inhibited the proliferation of VSMC and neointima formation induced by balloon aortic injury (by 66% and 79% respectively, P < 0.01). In addition, ET and AII attenuated the expression of HRG-1 in aorta and stimulated mitogen-activated protein kinase (MAPK) activity, while CGRP and Adm potentiated the expression of HRG-1 and inhibited MAPK.. ET and AII can stimulate the proliferation of injured intima while CGRP and Adm have an anti-hyperplasia effect after angioplasty. These 4 peptides are involved in the regulation of VSMC proliferation and affect the development of vascular restenosis by regulating the expression of HRG-1 and MAPK activity.

Topics: Adrenomedullin; Angioplasty, Balloon; Angiotensin II; Animals; Aorta, Thoracic; Calcitonin Gene-Related Peptide; Cell Division; Cells, Cultured; Coronary Restenosis; Endothelin-1; Male; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Vasodilator Agents

Endothelins are important vasoconstrictors and cellular-growth promoters. ETA-specific antagonists have been shown to reduce neointimal response to injury in some experimental angioplasty models. However, there is little information on the effects of dual ETA/ETB receptor blockers, such as bosentan, on neointimal proliferation following experimental coronary angioplasty.. Coronary injury was achieved by directional atherectomy in the left anterior descending artery of 20 pigs. Animals were randomly assigned to receive a daily dose of oral bosentan (30 mg kg-1) (group I, n = 10) or no treatment (group II, n = 10). At 4 weeks, arteries were processed for histomorphometry and endothelin characterization.. Vessel injury score was similar among the two groups. Overall, a linear correlation was found between injury and neointimal development (r = 0.57, P = 0.01). This correlation had a lower slope in group I compared with group II (P < 0.001), indicating a smaller amount of neointimal development for a similar degree of injury in bosentan-treated animals. Multivariate regression showed that neointimal response was reduced by oral treatment with bosentan (beta: -0.59 mm2, 95% CI: -1.11/-0.06 mm2). In addition, immunostaining revealed fewer positive endothelin areas in group I arteries.. Oral treatment with bosentan reduces neointimal development following coronary angioplasty in this experimental model.

Topics: Administration, Oral; Angioplasty; Animals; Antihypertensive Agents; Bosentan; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Immunohistochemistry; Sulfonamides; Swine; Tunica Intima

We sought to demonstrate, in an appropriate animal model, that co-medication with a transcription factor-blocking agent limits restenosis after percutaneous transluminal coronary angioplasty (PTCA).. Enhanced synthesis in the vessel wall of endothelin-1 (ET-1), a powerful co-mitogen for vascular smooth muscle cells, appears to be one mechanism that promotes restenosis after PTCA. Deformation-induced expression of prepro-ET-1 is governed by the transcription factor, activator protein-1 (AP-1).. An anti-AP-1 decoy oligodeoxynucleotide (dODN) strategy was devised in which the dODN-containing solution (20 nmol) was administered locally through a Dispatch catheter into the coronary arteries of hypercholesterolemic minipigs at the time of PTCA (AVE-GFX stent).. Treatment with an AP-1 dODN, mimicking the consensus binding site of the transcription factor, significantly reduced neointimal formation in the coronary arteries of hypercholesterolemic minipigs (n = 10 to 12), compared with vehicle-treated coronary arteries, after four weeks of follow-up (neointimal area 2.64 +/- 0.33 vs. 4.81 +/- 1.04 mm(2) [mean +/- SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 +/- 0.22 mm(2); n = 3) and correlated with a reduction in both nuclear translocation of AP-1 and ET-1 synthesis in the vessel wall 48 h after PTCA (n = 4). In contrast, an AP-1 mutant dODN, to which the transcription factor does not bind, showed no effect on neointimal formation at either time point (n = 3 to 7). Moreover, a consensus dODN directed against CCAAT/enhancer binding protein (C/EBP), another deformation-sensitive transcription factor, did not significantly affect neointimal formation after four weeks (n = 3).. These findings demonstrate the feasibility, efficacy and specificity of the anti-AP-1 dODN approach to the treatment of restenosis, which principally but not exclusively targets deformation-induced ET-1 synthesis in the vessel wall. Provided that these findings can be extrapolated to the situation of patients with coronary artery disease, the observed extent of the inhibitory effect of the AP-1 dODN treatment suggests that this co-medication may greatly reduce the incidence of in-stent restenosis.

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiac Catheterization; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Endothelin-1; Feasibility Studies; Hypercholesterolemia; Oligonucleotides; Swine, Miniature; Transcription Factor AP-1; Transcription Factors; Tunica Intima

The aim of the present study was to test whether oral dosing of an endothelin (ET) receptor antagonist was able to reduce restenosis in the model of stent-induced restenosis. After pigs underwent coronary artery catheterization they were randomly allocated either to controls or to treatment with the ET receptor antagonist BSF 208075. Thirty-seven pigs underwent percutaneous transluminal coronary angioplasty plus stent implantation; seven animals died of ventricular fibrillation due to procedure-related myocardial ischaemia. From the 30 surviving animals coronary arteries were sampled after 6 weeks of oral treatment with 10 mg/kg/day BSF 208075 or vehicle and histologically evaluated. Stent implantation had no effect on total coronary artery diameter, and media thickness was virtually identical in the two groups. However, neointimal thickness in the group treated with the ET receptor antagonist was significantly reduced, resulting in a significantly larger total coronary artery lumen in the treated group. As in the setting of stent implantation neither 'recoil' nor scar-related vascular remodelling can occur, this result allows the conclusion of a significant antiproliferative effect of ET receptor antagonism in pig coronary arteries.

Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Animals; Coronary Artery Disease; Coronary Restenosis; Endothelin Receptor Antagonists; Endothelin-1; Male; Models, Animal; Myocardial Ischemia; Propionates; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Stents; Swine