Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 is a potent vasoconstrictor and mitogenic peptide that is implicated in the atherosclerosis of apolipoprotein E-deficient mice and may promote atherogenesis in humans. We hypothesized that endothelin-1 might promote the adhesion of monocytes to endothelial cells, a key early event in atherosclerosis. We investigated the adhesion of primary human monocytes (isolated by elutriation) to human umbilical vein endothelial cell cultures after incubation with endothelin-1 (0.1 and 0.01 nM; approximately physiological concentrations), copper-oxidized low-density lipoprotein (LDL) (0.1 mg/ml) and a combination of the two. After a 4 h incubation with 0.1 or 0.01 nM endothelin-1 combined with oxidized LDL, adhesion was increased to 120+/-4% (P<0.001 compared with control) and 118+/-4% (P<0.002) respectively, whereas neither substance alone increased adhesion (92-104% of control values; not significant). Neither endothelin receptor A blockade nor co-incubation with anti-fibronectin antibody inhibited the pro-adhesive effects of endothelin-1 plus oxidized LDL (115+/-7% and 115+/-3% of control compared with 120+/-4% respectively; not significant). Endothelial cell expression of intercellular adhesion molecule-1, vascular adhesion molecule-1 and E-selectin were unchanged throughout the experiment. Therefore physiological concentrations of endothelin-1 and oxidized LDL may act synergistically to increase the adhesion of human monocytes to endothelial cells, contributing in part to the observed pro-atherogenic effects of endothelin-1.
 ...
PMID:Endothelin-1 plus oxidized low-density lipoprotein, but neither alone, increase human monocyte adhesion to endothelial cells. 1172 63

Three endothelin family peptides (endothelin-1, -2 and -3) exert an extremely potent and long-lasting vasoconstrictor action as well as other various actions through stimulating two subtypes of receptor (ETA and ETB). Vascular endothelial cells produce only endothelin-1. Although the pharmacological actions of exogenous endothelin-1 have been extensively analyzed, the physiological roles of endogenous endothelin-1 have long been obscure. Using potent and selective receptor antagonists, endothelin-1 has been demonstrated to contribute slightly to the maintenance of regional vascular tone. In gene-targeted mice, endothelin family peptides and their receptors have been shown to play an important role in the embryonic development of neural crest-derived tissues. In addition to its potent vasoconstrictor action, endothelin-1 has direct mitogenic actions on cardiovascular tissues, as well as co-mitogenic actions with a wide variety of growth factors and vasoactive substances. Endothelin-1 also promotes the synthesis and secretion of various substances including extracellular constituents. These effects of endogenous endothelin-1 would appear to be naturally concerned with the development and/or aggravation of chronic cardiovascular diseases, e.g. hypertension, pulmonary hypertension, vascular remodeling (restenosis, atherosclerosis), renal failure, and heart failure. A great many non-peptide and orally active endothelin receptor antagonists have been developed, and shown to exert excellent therapeutic effects in animal models as well as human patients with these diseases.
 ...
PMID:Basic and therapeutic relevance of endothelin-mediated regulation. 1172 53

Retinoids have been shown to inhibit cell growth, which can result in an anti-atherosclerotic action in the vasculature. Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced in endothelial cells, plays an important role in inducing proliferation of vascular smooth muscle cells. In this study, we investigated the effect of retinoids on the mRNA expression and transcriptional activity of the ET-1 gene in endothelial cells. All-trans retinoic acid (ATRA) suppressed ET-1 mRNA expression in cultured endothelial cells. Synthetic retinoids, Ch55 and Am580 (retinoic acid receptor (RAR) agonists) markedly enhanced this effect, and an RAR antagonist, LE540, blocked this inhibitory effect on ET-1 gene expression. ATRA did not change ET-1 mRNA half-life. Transfection experiments using 5 kb of the ET-1 promoter-reporter gene construct which contains 5 kb of the preproET-1 promoter revealed that ATRA and Ch55 suppressed ET-1 promoter activity, resulting in down-regulation of ET-1 gene transcription. Taken together, retinoids may be another modulator of endothelial cell function through regulation of vasoactive substances at the transcription level.
Atherosclerosis 2001 Dec
PMID:Retinoic acid suppresses endothelin-1 gene expression at the transcription level in endothelial cells. 1173 Aug 31

Comparative analysis of cytokines and sCAM secretion within the lymphocyte chromatin state are possible evidence of inflammatory reactions in atherosclerosis. Two types of response were studied: coagulation and fibrinolysis (incubation of blood clot within 6 hours at 37 degrees C) and standardized viscosimetric flow using a rotational viscometer (shear rate 100 l/s, 60 seconds at 37 degrees C, and incubation within 6 hours at 37 degrees C). Cytokines IL-1alpha, IL-1beta, IL-6, IL-8, IL-10 (Immunotech, France), endothelin-1, and soluble cell adhesion molecules (sCAM) sP- and sE-selectin, sICAM-1, and sVCAM-1 (R&D, UK) have been determined using ELISA kits (photometer, Biomek-1000, Beckman, USA). The chromatin of lymphocyte nuclei was studied using the computer TV morphodensitometry system DiaMorph (Russia) and smears dyed specifically for DNA. Correlational changes in morphodensitometric (MDM) parameters and cytokine and sCAM levels in two tests were compared to initial levels. After rheologic testing, lymphocyte nuclei as a whole had not changed, but chromatin activity had decreased. Reorganization of nuclei after the coagulation test was observed. Endothelin-1 and sP- and sE-selectin levels were not related to function of lymphocytes (by MDM data) as seen in both tests; it is probable that another cell-cell communication mechanism had been switched on. We established a strong correlation between chromatin activity of lymphocytes and the serum concentration of IL-1beta, IL-6, and IL-10, which are the active participants in the pro- and anti-inflammatory program in atherogenesis. Results are evidence of the role of lymphocytes in pro- and anti-inflammatory cytokine reactions and cytokine-like sCAM activity in atherosclerosis.
 ...
PMID:Chromatin image analysis provides new evidence of the relation of lymphocytes to cytokines and sCAM in the inflammatory nature of atherosclerosis. 1179 95

Atherosclerotic vascular disease remains the single most prevalent cause of death and morbidity in the western world. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that also possesses mitogenic activity on many cell types, including vascular smooth muscle cells. Raised plasma and tissue levels of ET-1 have been described in atherosclerosis in animal models and in man, suggesting that this peptide plays a pathophysiological role in this condition. Two main ET-1 receptors have been cloned (ET(A) and ET(B)). Mixed ET(A/B) and receptor subtype selective antagonists are now available. Since ET-1 is generally believed to be a 'pathophysiological peptide', we discuss the therapeutic potential of ET-1 antagonists in atherosclerosis and consider whether, at certain sites in this process, ET-1 may play a beneficial role. In such situations ET antagonism may be undesirable.
Atherosclerosis 2002 Feb
PMID:Endothelin-1 and atherosclerosis: potential complications associated with endothelin-receptor blockade. 1184 51

Endothelin-1 (ET-1) and oxidized low-density lipoprotein (ox-LDL) are associated with atherosclerosis and essential hypertension. We assessed the effect of mildly oxidized LDL (mox-LDL) and ox-LDL and their major oxidative components, i.e., reactive oxygen species (ROS), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with ET-1 on vascular smooth muscle cell (VSMC) proliferation. Growth-arrested VSMCs isolated from the rabbit aorta were incubated with different concentrations of LDL, mox-LDL, ox-LDL, hydrogen peroxide (H(2)O(2)) (a donor of ROS), LPC, or HNE with or without ET-1. DNA synthesis in VSMCs was measured by [(3)H] thymidine incorporation. Mox-LDL, ox-LDL, H(2)O(2), LPC, HNE, or ET-1 stimulated DNA synthesis in a dose-dependent manner. Maximal effect was observed at 5 microg/ml for mox-LDL (162%) or ox-LDL (154%), 15 microM LPC (156%), 5 microM H2O2 (177%), 1 microM HNE (144%), and 0.1 microM ET-1 (195%). By contrast, LDL was without any significant effect. When added together, there was no synergistic effect of LDL, H2O2, or HNE with ET-1 on DNA synthesis. However, the effect of mox-LDL (0.1 microg/ml), ox-LDL (0.5 microg/ml), or LPC (10 microM) was potentiated by ET-1 (114%-338%, 133%-425%, 118%-333%, respectively). The mitogenic effect of mox-LDL, ox-LDL, or LPC and their interaction with ET-1 were inhibited by defatted albumin (10 microg/ml), antioxidant N-acetylcysteine (400 microM), the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (1 microM). The ET(A/B) receptor antagonist TAK044 (1 microM) or the MAPK kinase inhibitor PD098059 (10 microM) inhibited the mitogenic effect of ET-1 and its interaction with mox-LDL, ox-LDL, or LPC. The synergistic interaction of mox-LDL, ox-LDL, or LPC with ET-1 was completely reversed by the combined use of N-acetylcysteine and TAK044. Our results suggest that mox-LDL, ox-LDL, and their major phospholipid component LPC act synergistically with ET-1 in inducing VSMC proliferation by way of the activation of redox-sensitive and MAPK pathways.
 ...
PMID:Lysophosphatidylcholine is a major contributor to the synergistic effect of mildly oxidized low-density lipoprotein with endothelin-1 on vascular smooth muscle cell proliferation. 1186 25

Endothelin-1 (ET-1) is an endothelial-derived 21-amino-acid peptide with potent vasoconstrictor and mitogenic properties implicated in several cardiovascular disorders. To evaluate the plasma ET-1 response to mental stress in patients with intermittent claudication, plasma endothelin concentrations were measured by radioimmunoassay in 15 claudicant outpatients (13 men and 2 women; mean age 62 +/- 4 years) and in 15 sex- and age-matched healthy control subjects (12 men and 3 women; mean age 60 +/- 8 years) before and after mental arithmetic performed for 10 minutes. Venous blood samples were drawn from an antecubital vein at baseline, at the end of the mental arithmetic, and at 10 minutes of recovery. Baseline ET-1 values were higher in patients with intermittent claudication as compared with control subjects (4.5 +/- 0.5 pmol/L and 2.2 +/- 0.3 pmol/L, respectively, p < 0.0001). At the end of mental stress, ET-1 levels rose significantly in both groups from baseline (p < 0.001) reaching a higher value in patients with intermittent claudication than in control subjects (5.6 +/- 0.7 pmol/L and 2.4 +/- 0.4 pmol/L, respectively, p < 0.0001). The percent increases (delta%) in ET-1 plasma concentrations from baseline in response to mental stress were significantly greater in claudicant patients than in control subjects (+23 +/- 9% and +9 +/- 7%, respectively, p < 0.0001). ET-1 plasma concentrations returned to baseline values similarly in both groups at minute 10 of the recovery period. These findings show that acute mental stress causes an exaggerated release of ET-1 in patients with intermittent claudication and suggest that this could be a potential pathophysiological mechanism through which mental stress may trigger adverse acute cardiac events and accelerate progression of atherosclerosis in these patients.
 ...
PMID:Exaggerated endothelin release in response to acute mental stress in patients with intermittent claudication. 1214 42

Endothelin-1 (ET-1) may be involved in the development and progression of atherosclerosis. Furthermore, endothelin receptor blockade was shown to reduce the formation of atherosclerotic lesions in experimental studies. Another potent pro-atherosclerotic risk factor is oxidized low-density lipoprotein (oxLDL). Endothelial cells mediate the uptake of oxLDL by the recently identified lectin-like oxLDL receptor-1 (LOX-1), which accumulates in atherosclerotic lesions. In the present study, we analysed the effects of ET-1 on oxLDL uptake and LOX-1 expression in primary cultures of human umbilical vein endothelial cells (HUVEC). ET-1 stimulated uptake of oxLDL in HUVEC, which reached a maximum after 1 h. In further studies, we found a similar induction of LOX-1 mRNA and protein expression in response to ET-1. The augmented oxLDL uptake and the increased LOX-1 expression in response to ET-1 are mediated by the endothelin receptor B. Our data support a new pathophysiological mechanism by which locally and systemically increased ET-1 levels, e.g. in hypertensive patients, could promote LOX-1-mediated oxLDL uptake in human endothelial cells. This mechanism could promote the development and progression of endothelial dysfunction and atherosclerosis. In addition, endothelin receptor blockade could be considered as a new anti-atherosclerotic therapeutic principle.
 ...
PMID:Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1. 1219 44

Endothelin is a potent vasoconstrictor peptide isolated from endothelial cells and it induces smooth muscle cell proliferation. Endothelin-1 secretion is increased in atheroma and induces deleterious effects such as vasospasm and atherosclerosis. Oxidized low-density lipoproteins (LDLs) induce atherosclerosis in the vascular wall, as well as endothelin-1 secretion in endothelial cells and are activators of both peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma. PPAR-alpha (fibric acids) and PPAR-gamma (glitazones) activators are used to treat dyslipoproteinemias and type 2 diabetes, respectively. Furthermore, these drugs induce numerous pleiotropic effects, such as inhibiting thrombin-induced endothelin-1 secretion in endothelial cells. This study shows that both PPAR-alpha (Wy 14643) and PPAR-gamma activation (rosiglitazone) partially inhibit oxidized LDL-induced protein kinase C activity and endothelin-1 secretion in endothelial cells at the transcriptional levels and suggests that synthetic PPAR activators are stronger PPAR activators than oxidized LDL. This study also suggests that fibrate and glitazone treatments should have beneficial effects on the vascular wall by reducing endothelin-1 secretion and the resulting vasospasm and atherosclerosis.
 ...
PMID:Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. 1245 15

Endothelial function deteriorates with aging. On the other hand, exercise training improves the function of vascular endothelial cells. Endothelin-1 (ET-1), which is produced by vascular endothelial cells, has potent constrictor and proliferative activity in vascular smooth muscle cells and, therefore, has been implicated in regulation of vascular tonus and progression of atherosclerosis. We previously reported significantly higher plasma ET-1 concentration in middle-aged than in young humans, and recently we showed that plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans. We hypothesized that plasma ET-1 concentration increases with age, even in healthy adults, and that lifestyle modification (i.e., exercise) can reduce plasma ET-1 concentration in previously sedentary older adults. We measured plasma ET-1 concentration in healthy young women (21-28 yr old), healthy middle-aged women (31-47 yr old), and healthy older women (61-69 yr old). The plasma level of ET-1 significantly increased with aging (1.02 +/- 0.08, 1.33 +/- 0.11, and 2.90 +/- 0.20 pg/ml in young, middle-aged, and older women, respectively). Thus plasma ET-1 concentration was markedly higher in healthy older women than in healthy young or middle-aged women (by approximately 3- and 2-fold, respectively). In healthy older women, we also measured plasma ET-1 concentration after 3 mo of aerobic exercise (cycling on a leg ergometer at 80% of ventilatory threshold for 30 min, 5 days/wk). Regular exercise significantly decreased plasma ET-1 concentration in the healthy older women (2.22 +/- 0.16 pg/ml, P < 0.01) and also significantly reduced their blood pressure. The present study suggests that regular aerobic-endurance exercise reduces plasma ET-1 concentration in older humans, and this reduction in plasma ET-1 concentration may have beneficial effects on the cardiovascular system (i.e., prevention of progression of hypertension and/or atherosclerosis by endogenous ET-1).
 ...
PMID:Aerobic exercise training reduces plasma endothelin-1 concentration in older women. 1261 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>