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

Hypoxia has profound effects on blood vessel tone. Acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia causes smooth muscle cell replication and extracellular matrix accumulation resulting in vessel wall remodeling. The cellular responses to hypoxia involve complex cell-cell interactions mediated by the release of growth factors, cytokines and biological messengers. We have reported that hypoxia increases the expression of a number of genes encoding vascular cell mitogens produced by endothelial cells: platelet-derived growth factor B (PDGF-B); endothelin-1 (ET-1); and vascular endothelial growth factor (VEGF). A 28-bp enhancer in the 5' upstream region of the VEGF gene mediates the expression of VEGF by endothelial cells under conditions of hypoxia. Hypoxia, however, has opposite effects on the vasodilator nitric oxide (NO); hypoxia suppresses both the transcriptional rate of the endothelial nitric oxide synthase gene and the stability of its mRNA. These endothelial-dependent processes would lead to vessel wall remodeling characteristic of a number of diseases from atherosclerosis to pulmonary hypertension. The smooth muscle cell also responds to hypoxia. It increases the transcriptional rate of the heme oxygenase gene-1 responsible for the breakdown of heme to carbon monoxide (CO) and biliverdin. CO is a vasodilator with properties similar to the well-studied molecule NO. CO suppresses the production of ET-1 and PDGF-B by endothelial cells. The regulated production of NO and CO under hypoxia, therefore, results in complex feedback loop interactions leading to altered smooth muscle cell growth in an autocrine and paracrine manner.
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PMID:Mechanisms by which oxygen regulates gene expression and cell-cell interaction in the vasculature. 902 18

The endothelium is involved in both the physiological regulation of vascular tone and the structural transformation of the vessel under pathological conditions. Under physiological conditions, endothelial cells continuously secrete nitric oxide (NO), which relaxes smooth muscle cells and ensures vessel patency. Damaged or excessively activated endothelial cells can also secrete vasoconstrictor factors, the best known of which is endothelin-1 (ET-1), as well as factors that affect the differentiation and growth of vascular smooth muscle cells. How endothelial cell damage contributes, under pathological conditions, to vascular disease can best be illustrated in patients with diabetes mellitus, in whom there are pronounced changes in endothelial cell structure and function. Endothelial cells also interact with cells in the bloodstream, ET-1 and other factors are released from endothelial cells into the bloodstream, where their chemotactic action can induce leucocytes and platelets to migrate to the endothelial wall. Endothelial cells induce adhesion by expression of specific surface adhesion molecules (selectins, integrins and a supergene family of immunoglobulins) that can interact with ligands on the leucocytes and platelets. The expression of adhesion molecules is increased in endothelial cells chronically damaged by risk factors for atherosclerosis. The disturbed permeability of the endothelial layer in patients with diabetes mellitus and/or hyperlipidaemia leads to an increased influx of substances from the circulation into the vessel wall. In addition, endothelial cell dysfunction can lead to accelerated intravessel blood coagulation. It is evident that the endothelium plays a central role in many of the early pathophysiological processes involved in atherosclerosis. It is therefore important to investigate the effects of antiatherosclerotic therapy on endothelial cell function and cell-to-cell interactions. Until recently, little was known about the direct effects of calcium antagonists on endothelial cell function. Recent studies, including two clinical studies, indicate that calcium antagonists primarily affect interactions of endothelial cells, smooth muscle cells, monocytes and platelets, which play a central role in the early phases of the development of atherosclerosis, whereas the protective effect of these agents on the vascular system appears to be low at later stages.
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PMID:Endothelial function. General considerations. 903 50

The endothelium participates in the control of coronary vascular tone and growth through the release of vasodilating and growth-inhibiting factors such as nitric oxide (NO) and C-type natriuretic peptide (CNP), and vasoconstricting and growth-promoting substances such as endothelin-1 (ET-1). Abnormalities in NO and/or CNP generation or actions have been demonstrated in various cardiovascular pathophysiological states, specifically atherosclerosis, congestive heart failure, hypertension and hypercholesterolaemia. Moreover, an increase in plasma ET-1 levels has also been reported in these disease states. When these observations are considered together, these states may be characterised by an attenuated release or action of NO and/or CNP, together with an augmented release of ET-1. Thus, an imbalance between these opposing factors may contribute to the alteration in vascular tone and the vascular remodelling characteristics of cardiovascular disease. The following article summarises the present knowledge of endothelial control of the coronary circulation and derangements associated with coronary endothelial dysfunction.
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PMID:Coronary endothelial function in health and disease. 903 52

Our previous studies demonstrated the morphological heterogeneity of endothelial cells (ECs) and the emergence of large multinucleated ECs in human and animal atherosclerotic lesions. To investigate the functional alteration of ECs in diet-induced atherosclerosis, immunoreactive endothelin-1 (irET-1) release by ECs of the rabbit aorta was correlated with scanning electron microscopy. Rabbits were fed a cholesterol diet for 12 weeks: by scanning electron microscopy, the area of ECs in the aorta increased in the hypercholesterolemic (HC) group as atherosclerosis progressed. Cultured ECs of the HC group released significantly more irET-1 than ECs of the control. The plasma irET-1 level was also elevated in the HC group. The results obtained suggest that accelerated secretion of ET-1 by ECs contributes to the development of atherosclerotic vascular lesions.
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PMID:Diet-induced hypercholesterolemia increases endothelin-1 release by aortic endothelial cells. 915 27

Endothelins are ubiquitously produced 21-amino-acid peptides that were discovered as an endothelial product and may play important roles in cardiovescular physiology and pathophysiology. The main endothelin produced by the endothelium is endothelin-1. The vasoconstrictor role of endothelins may participate in blood pressure elevation and vascular hypertrophy in salt-dependent models of hypertension (deoxycorticosterone acetate-salt hypertensive rats, spontaneously hypertensive rats treated with deoxycorticosterone, acetate and salt, and Dehl salt-sensitive rats), and in stroke-prone spontaneously hypertensive rats. In humans, endothelins may play important roles in moderate to severe essential hypertension, and in the hypertension of African-Americans. Endothelins may be involved in cardiac hypertrophy, and there is increasing evidence of their participation in heart failure, in which acute endothelin antagonism in humans exerts beneficial effects. Endothelin expression is enhanced in smooth muscle cells migrating into the intima of arteries in atherosclerosis, suggesting a role in atherogenesis. Endothelin may participate as a vasoconstrictor in coronary artery disease, and as a contributor to intimal proliferation in restenosis after coronary angioplasty. In patients with myocardial infarction, cardiac production of endothelin is increased, particularly in those with cardiogenic shock. There is a potential for participation of endothelins in vasospasm accompanying stroke or subarachnoid hemorrhage: in the latter, endothelin antagonism has shown beneficial effects in experimental models. In neonatal and in primary pulmonary hypertension, endothelin expression is enhanced, and in experimental models endothelin antagonism resulted in favorable responses. Systemic sclerosis is another, peripheral, form of vascular disease in which endothelin may play a role and in which endothelin antagonism may be an interesting therapeutic alternative. The pathophysiologic role of endothelins is becoming increasingly apparent in cardiovascular disease, generating interesting potential therapeutic targets for the use of endothelin antagonists or endothelin-converting enzyme inhibitors.
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PMID:Clinical significance of endothelin in cardiovascular disease. 926 47

Significant new findings in the last decade have demonstrated that the vascular endothelium is an important regulatory organ in maintaining cardiovascular homeostasis and that endothelial dysfunction is present in several cardiovascular diseases. With the production of multiple vasoactive substances the normal endothelium modulates the tone of the underlying vascular smooth muscle. These include endothelium-derived relaxing factors such as prostacyclin (PG1(2)), nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) and vasoconstrictors such as endothelin-1 and angiotensin II. The antiplatelet, antithrombotic and antifibrinolytic properties of the normal endothelium contribute to the maintenance of the fluidity of the blood. Activation or injury to the endothelial cells disrupts the function of the endothelial cells leading to the development of endothelial dysfunction. Endothelial dysfunction is accompanied by vasospasm, thrombosis, and atherosclerosis. It is present in cardiovascular diseases such as hypertension, atherosclerotic heart diseases, congestive heart failure and many others. It has been shown that some therapeutic effects of drugs such as angiotensin-enzyme inhibitors is in part due to the overcoming of endothelial dysfunction.
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PMID:The endothelium in health and in cardiovascular disease. 928 90

Endothelin-1 is a vasoactive peptide produced by endothelial cells. Endothelin-1 exerts potent vasoconstrictory effects upon vascular smooth muscle cells, and it may play a role in the pathogenesis of several cardiovascular disorders such as atherosclerosis and ischemic conditions. Besides the investigation of its biological effects, knowledge about cellular mechanisms of the synthesis, signal transduction pathway(s) and receptor-mediated actions on target cells is mandatory for the development of pharmacological strategies in the treatment of cardiovascular disease. In this review cellular mechanisms of endothelial endothelin-1 synthesis and release are discussed.
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PMID:[Cellular mechanisms of endothelial endothelin synthesis]. 938 81

An increasing body of evidence indicates that the endothelium is crucially involved in the regulation of coronary blood flow and cardiac function. Injury to the endothelium precipitates atherosclerosis by leading to smooth-muscle-cell migration and proliferation, induction of expression of growth factors and impairment in the plasmatic coagulation and endogenous fibrinolysis system. Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and trafficking blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors, such as angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. Modern therapeutic strategies in coronary artery disease focus on preserving or restoring endothelial integrity. Whereas nitrates partly substitute deficient endogenous nitric oxide, calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. Furthermore, newly developed specific endothelin antagonists will provide us with greater insight into the beneficial effects of restoring endothelial dysfunction in cardiovascular disease. Thus, drugs can directly affect endothelial function, prevent the action of endothelial mediators, substitute for deficient endothelial factors or indirectly exert protective effects by interfering with cardiovascular risk factors.
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PMID:The endothelium in coronary artery disease. 939 88

The vasoactive hormone angiotensin II (Ang II) can stimulate vascular smooth muscle cell (SMC) hypertrophy and proliferation; thus, it may have an important role in the pathogenesis of hypertension, atherosclerosis and restenosis. Several studies have indicated that Ang II bioactivity on SMC may depend, at least in part, on its ability to induce the expression of polypeptide growth factors that can function in an autocrine manner. Here we report that Ang II treatment of rat aortic SMC increases fibroblast growth factor-2 (FGF-2) but not FGF-1 mRNA levels. Increased FGF-2 mRNA expression is first detectable at 30 min after Ang II addition and maximal levels are present at 8 hr. Ang II induction of FGF-2 mRNA levels is dependent on de novo RNA and protein synthesis. The Ang II effect can be blocked by treatment with either the Ang II type 1 receptor-selective antagonist CI-996 or the tyrosine kinase inhibitor genistein. The potent vasoconstrictor and SMC mitogen endothelin-1 can also induce FGF-2 mRNA levels in rat aortic SMC. These results indicate that FGF-2 gene expression is up-regulated by two distinct vasoactive peptides implicated in vascular SMC growth control in vivo.
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PMID:Angiotensin II and endothelin-1 increase fibroblast growth factor-2 mRNA expression in vascular smooth muscle cells. 943 36

The relationship between carotid atherosclerosis and plasma endothelin-1 (ET-1) concentration was studied in senile patients with essential hypertension. A total of 212 patients (83 M, 129 F; mean age, 63 years) with essential hypertension (WHO stage I-II), and 109 age-matched control subjects (mean age, 61 years) were enrolled in the study. The maximum thicknesses of the intima-media complex (IMTmax) in the right common carotid artery (CCA) and the right internal carotid artery (ICA) was measured by B-mode ultrasonography, and ET-1 was measured by enzyme immunoassay. ET-1 levels were significantly higher in the hypertensive patients than in the control subjects. In middle-aged patients (35-64 years old), IMTmax values of the ICA in patients with high ET-1 concentrations (ET-1 > or = 1.71 pg/ml) were significantly higher than in patients with normal ET-1 concentrations (ET-1 < 1.71 pg/ml). However, the IMTmax of the CCA did not show a similar correlation. In senile patients (65-83 years old), both the CCA and ICA IMTmax values were significantly higher in patients with high ET-1 concentrations than in those with normal ET-1 concentrations. These results indicate that high ET-1 levels in middle-aged patients with essential hypertension may play a role in the progression of ICA atherosclerosis. High ET-1 levels in senile patients with essential hypertension may cause progression of atherosclerosis in both the ICA and CCA.
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PMID:[Relationship between carotid atherosclerosis and plasma endothelin-1 concentration in senile patients with hypertension]. 949 68


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