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)

Atherosclerosis is a major risk factor for both myocardial infarction and stroke. A key aspect of this disease is the imbalance of vasoactive factors. In this concise review, we focus on the role of endothelin-1 in the atherosclerotic process and other vasculopathies. Previously, we have demonstrated that there is a correlation between the expression of endothelin and the underlying atherosclerotic lesion. Immunoreactivity was observed for both ET-1 and ECE-1 in endothelial cells, smooth muscle cells, and macrophages within lesions. Endothelin's role in atherosclerosis must extend from its varying physiological activities, including vasoconstriction, mitogenesis, neutrophil adhesion, and platelet aggregation, and hypertrophy, as well as its propensity to induce the formation of reactive oxygen species. We also discuss regulation of endothelin by angiotensin II, reactive oxygen species, thrombin, aging, and LDL in the cardiovascular system. Finally, we demonstrate the role of endothelin in pulmonary hypertension and transplant associated vasculopathy.
 ...
PMID:Endothelin-1 in atherosclerosis and other vasculopathies. 1283 69

Endothelins (ETs) are a family of potent peptidic vasoconstrictors that have been implicated in the pathogenesis of many cardiovascular disorders such as hypertension, myocardial infarction, congestive heart failure, atherosclerosis and restenosis. Suppression of the production of these peptides by inhibitors of endothelin-converting enzyme-1 (ECE-1), which is involved in the final step of post-translational processing of ETs, may therefore have beneficial effects for the treatment of these disorders. A number of non-selective and selective ECE-1 inhibitors have been identified, and this article reviews the pharmacological effects of these agents in animal models of cardiovascular diseases and presents available clinical data.
 ...
PMID:Utility of endothelin-converting enzyme inhibitors for the treatment of cardiovascular diseases. 1458 51

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.
 ...
PMID:Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. 1472 28

Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (" big endothelins") which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system.
 ...
PMID:[What is the role of endothelin system?]. 1506 80

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65+/-1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.
 ...
PMID:Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects. 1656 85

Endothelin-converting enzyme (ECE-1) is a critical enzyme in the production of the potent vasoconstrictor peptide endothelin (ET-1). It has previously been shown that the levels of both ET-1 and ECE-1 are raised in atherosclerosis, but the possible relevance of the isoforms of ECE-1 in these changes has not yet been investigated. The aim of this study was to examine the expression of the ECE-1a and ECE-1c isoforms in human atherosclerotic pathologies. Immunohistochemical analysis was carried out on sections from atherosclerotic and non-atherosclerotic vascular tissue using a combination of ECE-1 isoform-specific antibodies, anti-alpha-actin antibodies to identify smooth muscle cells (SMC) and anti-CD68 antibodies to identify macrophages. ECE-1 isoform expression was also examined in cultured SMC and in macrophages isolated from human blood. Results indicated differences in isoform expression in atherosclerotic lesions, with distinct patterns of staining for ECE-1a and ECE-1c. ECE-1c immunoreactivity was seen in macrophages, and also correlated with actin staining. ECE-1a was also localized to macrophages and SMC. Results of this study suggest that these local changes influence the expression patterns of the ECE-1 isoforms within individual cell types. Correlation of these isoform expression patterns with the stage of atherosclerosis could provide novel indicators of disease progression.
 ...
PMID:Expression and localization of human endothelin-converting enzyme-1 isoforms in symptomatic atherosclerotic disease and saphenous vein. 1674 Oct 1

Endothelin-1 (ET-1) exerts multiple biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by ET-converting enzymes (ECE), chymases (CMAs), and non-ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET-1, and the inhibition of ECE-1. ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET-1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of preproET-1, ECE-1, CMA, ET(A) and ET(B) receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. Thus, even though ET antagonists are being used for the treatment of pulmonary hypertension, there is no convincing evidence for a role of SNPs in affecting the therapeutic strategies.
 ...
PMID:Genetic variation in the endothelin system: do polymorphisms affect the therapeutic strategies? 1685 33

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).
 ...
PMID:Endothelin. 1699 23

Cardiovascular diseases (CDs) are among the most encountered pathologies in western countries; with obesity reaching pandemic proportions, they are soon to become a worldwide problem. High blood pressure is the main risk factor for CDs, and its tight control is an imperative for the treatment of complications such as renal diseases, heart failure, and atherosclerosis. Blood homeostasis and vascular tone are regulated through at least 3 major closely interrelated pathways in which zinc metallopeptidases modulate the concentration of vasoactive mediators. Those extensively studied vasopeptidases were therefore rapidly targeted with specific inhibitors in order to control the levels of vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [bradykinin (BK) and atrial natriuretic peptide (ANP)], thereby controlling blood pressure. The first class of inhibitors to be developed were against angiotensin-converting enzyme (ACE), recently followed by dual inhibitors of ACE/neprylisin (NEP), NEP/endothelin-converting enzyme (ECE), and finally triple ACE/NEP/ECE inhibitors. The dual and triple inhibitors are defined as vasopeptidase inhibitors (VPI). In addition to their ability to effectively lower blood pressure in hypertensive patients, drugs targeting these enzymes also displayed antiinflammatory and antifibrotic activities. The major point emerging from recent studies undertaken to improve the management of CDs is that the combined action of different therapeutic strategies (ie, simultaneous modulation of several neurohumoral mediators) shows better results than conservative therapeutic approaches. In this review, we historically present the advances made in the comprehension of the different mechanisms of blood pressure regulation and some of the drugs that arose from this understanding.
 ...
PMID:Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. 1787 51

The present study was designed to investigate whether the aqueous extract of rhubarb (AR) could prevent the development of atherosclerosis through regulating vascular inflammatory processes in rats fed with an atherogenic diet. AR significantly reduced plasma low-density lipoprotein-cholesterol, and increased plasma high-density lipoprotein-cholesterol in rats fed with an atherogenic diet. AR inhibited vascular expressions of endothelin-1 (ET-1) and endothelin-converting enzyme (ECE) induced in rats with an atherogenic diet. On the other hand, AR augmented the vascular expression of endothelial nitric oxide synthase (ecNOS) and restored vascular nitric oxide (NO) production. Furthermore, AR suppressed the elevated expression of vascular nuclear factor-kappaB (NF-kappaB) p65 as well as adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in rats fed with an atherogenic diet. Also, AR decreased endothelial expression of ICAM-1 and ET-1 in aorta. These results suggest that AR suppresses the development of atherosclerosis in the atherogenic-diet rat model through inhibiting vascular expressions of proinflammatory and adhesion molecules via the regulation of nitric oxide and endothelin system.
 ...
PMID:Anti-atherogenic effects of the aqueous extract of rhubarb in rats fed an atherogenic diet. 1854 88


<< Previous 1 2 3 Next >>