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)

Endothelial dysfunction is an early event in atherosclerosis and could be considered a response to the injury induced by major risk factors. There is evidence that endothelial dysfunction is intimately involved in the onset and the progression of cardiovascular disease through abnormalities in the production, release or degradation of endothelium-derived factors, mainly nitric oxide and endothelin 1. Several reports have shown that drugs of the statin class could have multiple beneficial effects related to endothelium-mediated vasoactive, antithrombotic, antiproliferative and anti-inflammatory actions. Thus, the question arises of whether endothelial cells are the main target of statin therapy, in the setting of both hypercholesterolemia and normocholesterolemia. Experimental and clinical studies are reported that could support this hypothesis.
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PMID:HMG-CoA reductase inhibitors: Is the endothelium the main target? 1138 85

Endothelins, nitric oxide, and oxygen-derived free radicals decisively regulate vascular tone. An imbalance in the biosynthesis of these substances in pathophysiologic conditions may trigger vasospasm and promote the development of atherosclerosis. Previous studies have shown that oxygen-derived free radicals can increase the synthesis of endothelin-1 in cultured endothelial cells. Interestingly, conditions of increased oxidative stress within smooth muscle cells as induced by angiotensin II infusion or hypercholesterolemia have been shown to be associated with increased autocrine synthesis of endothelin-1. Because endothelin-1 formed in smooth muscle cells can trigger hypersensitivity to vasoconstrictors, we tested whether oxidative stress per se may affect endothelin expression in vascular smooth muscle cells. Cultured human coronary artery smooth muscle cells were exposed to oxidative stress generated by the xanthine/xanthine oxidase reaction or by hydrogen peroxide. Preproendothelin-1 mRNA content was quantitated by means of quantitative polymerase chain reaction and endothelin-1 protein was measured by radioimmunoassay. Incubation with xanthine/xanthine oxidase significantly increased preproendothelin-1 mRNA synthesis, whereas GAPDH remained unchanged. Likewise, xanthine/xanthine oxidase also led to a dose-dependent increase of intracellular endothelin-1. The increase in ET-1 expression induced by xanthine/xanthine oxidase was significantly inhibited by superoxide dismutase but not by catalase. We conclude that oxygen-derived free radicals can stimulate the synthesis of endothelin-1 in endothelial and vascular smooth muscle cells by increasing preproendothelin-1 mRNA content and that this effect is mediated predominantly by superoxide anions. We therefore have identified a new mechanism in the interaction of oxidative stress and endothelin-1 expression in smooth muscle cells that may have important implications in diseases such as atherosclerosis and hypertension.
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PMID:Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells. 1144 2

The aim of the study was to assess the plasma levels of endothelial injury markers in children from families with high risk of premature coronary heart disease (CHD) without other common CHD risk factors (hyperlipidaemia, obesity, hypertension, low physical activity). The study comprised 48 children, including 24 children from high-risk families (HR), according to the NCEP (National Cholesterol Education Programme) criteria: one or two parents had clinical manifestation of cardiovascular disease before the age of 65 years (mother) or 55 years (father). The control group included 24 healthy children with no familial history of cardiovascular disease. All the children were normolipidaemic according to the NCEP and the European Atherosclerosis Society criteria for children aged 2-19 years. In the HR group, the concentration of vWf was significantly elevated in comparison to that in the control group (p<0.0001). Plasma concentrations of ET-1 and TxB2 did not differ significantly between the HR group and the controls. Plasma concentrations of the 6-ketoPGF1alpha in the HR group and in the respective age and gender HR subgroups were significantly lower compared with those of the control group (p<0.00005). Concentration of vWf in the HR group was negatively correlated with the concentration of 6-ketoPGF1alpha (r = -0.47; p<0.05) and positively correlated with TxB2 (r=0.39; p<0.01). In a logistic regression analysis, we found that the 6-ketoPGF1alpha concentration in the lower quartile (< 16.1 pmol/L) was associated with a 3.4-fold odds of inclusion in the high-risk group versus the upper quartile (>23.0 pmol/L).
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PMID:Plasma levels of von willebrand factor, endothelin-1, prostacyclin and thromboxane in children from families with high risk of premature coronary artery disease. 1146 46

Endothelin (ET)-1, a 21-amino acid peptide, is the predominant isoform of the endothelin peptide family. ET-1 is ubiquitously expressed and stimulates vasoconstriction and cell proliferation. Enzymes such as endothelin converting enzymes (ECE), chymases, and non-ECE metalloproteinases contribute to the synthesis of ET-1, which is regulated in an autocrine fashion in vascular and nonvascular cells. Endothelin ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of nitric oxide and prostacyclin, and inhibition of ECE-1 expression. Most cardiovascular diseases, such as arterial hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, pulmonary hypertension, and renal failure are associated with local activation of the endothelin system. Experimental studies and first clinical trials suggest that ET-1 is importantly involved in the functional and structural changes in the cardiovascular system, and that many of the actions of ET-1 are mediated through pressure-independent mechanisms. Endothelin antagonists promise to be successful as a new class of drugs for the treatment of cardiovascular diseases.
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PMID:The therapeutic potential of endothelin receptor antagonists in cardiovascular disease. 1147 15

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since plasma endothelin concentrations were released from vascular endothelial cells, we have investigated the possible relationship between endothelin 1 (ET-1) and arterial wall thickness. Ninety-eight patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 50 non-diabetic subjects were studied. After an overnight fast, blood was taken for ET-1, glucose, HbA1c, lipids, insulin and C-peptide. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by B-mode ultrasound. ET-1 levels were significantly elevated in diabetic patients with IMT>1100 microm, 8.3 pmol/l (5.2-12.9) compared with control subjects, 7.6 pmol/l (5.0-11.0), p<0.01 and with diabetic subjects with IMT<500 microm, 7.43 pmol/l (4.8-11.1), p<0.01. The diabetic (IMT>1100 microm) study group had also significantly higher levels of insulin, 102.8 +/- 46.4 pmol/l vs control subjects, 77.5 +/- 32.4 pmol/l, p<0.01. In diabetic subjects, no correlation was found between ET-1 and IMT with glucose, HbA1c, lipids, age or duration of diabetes, respectively. We conclude that ET-1 levels are elevated in Type 2 diabetic patients with increased IMT. Thus providing further support for the role of endothelin in atherosclerosis.
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PMID:Plasma levels of endothelin and early carotid atherosclerosis in diabetic patients. 1175 70

An increased thickness of the carotid artery wall is thought to be a sign of early atherosclerosis. Since vascular endothelium is the site of formation of several substances, we have investigated the rate of progression of carotid atherosclerosis and the contribution of endothelin (ET-1), lipid peroxides [measured as thiobarbituric acid reacting species (TBARS)] and 6-keto-Prostaglandin-F1A (6-keto-PG-F1A) at baseline and after 30-months. Fifty patients with Type 2 diabetes without evidence of macroangiopathy, hypertension, proteinuria or proliferative retinopathy, and 27 healthy, non-diabetic persons were studied. Arterial wall thickness was measured as the mean of the maximum intimal-medial thickness (IMT) in 16 carotid segments by b-mode ultrasound. The IMT values was significantly increased in diabetic subjects (at baseline: 1110 +/- 310 microm, after 30 months: 1260 +/- 280 microm, p < 0.01), but not in control subjects (1100 +/- 280 microm, 1200 +/- 290 microm, respectively). At baseline time both groups had similar levels of ET-1, TBARS and 6-keto-PG-F1A. In 30-months follow-up, the ET-1 level 8.0 pmol/l (5.8-10.7) was significantly elevated in diabetic subjects, compared with the level at baseline time 7.43 pmol/l (4.8-11.1) p < 0.01. No significant differences were found in the other examined parameters in the studied groups. Although insulin levels remained unchanged in the two studied groups, in 30 months follow-up, the insulin level in the diabetic subjects, 92.4 +/- 35.1 pmol/l was significantly elevated compared with those of control subjects 76.0 +/- 31.0 pmol/l, p < 0.05. In conclusion, endothelis is the main associate of the change of IMT value over 30 months in diabetic patients, in whom the extent of atherosclerosis was significantly greater than in control subjects.
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PMID:Progression of carotid atherosclerosis and the role of endothelin in diabetic patients. 1175 71

We studied the association of endothelin (ET)-1 with carotid atherosclerosis and asymptomatic cerebrovascular lesions in patients with essential hypertension. Neurologically normal patients with essential hypertension (n=293; 138 male, 155 female; mean age, 65 years) and age-matched control subjects (n=242) were studied with B-mode ultrasonography of the common and internal carotid arteries and magnetic resonance imaging of the brain. Plasma ET-1 was measured by enzyme immunoassay. Hypertensive patients were divided into groups with carotid plaques and low ET-1 concentrations (< 0.75 pg/ml; PL group); carotid plaques and mid-range ET-1 (0.75 to 1.55 pg/ml; PM group); carotid plaques and high ET-1 (> or = 1.55 pg/ml; PH group); no plaques and low ET-1 (NPL); no plaques and mid-range ET-1 (NPM); and no plaques and high ET-1 (NPH). Overall, ET-1 concentrations were significantly higher in patients than in control subjects. Carotid plaque prevalence was significantly related to ET-1 in hypertensive patients. ET-1 showed a significant positive relationship with the number of asymptomatic lacunar infarcts of the brain in hypertensive patients with carotid plaques (rho=0.48, p<0.001). No significant relationship was seen between ET-1 and periventricular hyperintensity scores in patients with plaques. ET-1 did not show a relationship to either brain lesion type in patients without carotid plaques. Thus, ET-1 may foster asymptomatic lacunar cerebral infarcts by promoting carotid atherosclerosis in patients with essential hypertension.
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PMID:Associations of plasma endothelin concentration with carotid atherosclerosis and asymptomatic cerebrovascular lesions in patients with essential hypertension. 1176 25

Endothelin (ET)-1 is an endothelium-derived peptide with potent vasoconstrictor and proliferative properties. The ET system is activated in several cardiovascular disease states associated with functional and structural vascular changes, including hypertension and heart failure. The two ET receptor subtypes are known as ET(A)R and ET(B)R. The former is located mainly on vascular smooth muscle cells and is responsible for mediating vasoconstriction and proliferation. The latter is present predominantly on endothelial cells and mediates vasorelaxation as well as ET-1 clearance. Activation of smooth muscle ET(B)R causes vasoconstriction. Selective ET(A)R antagonists as well as nonselective ET(A)R-ET(B)R antagonists have been developed. Studies with animal models and early-phase clinical trials provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension, and atherosclerosis. However, the complexity of biologic effects mediated by two different receptor subtypes complicates therapy with selective versus nonselective ET receptor antagonists. In addition to subtype selectivity and potency, changes in receptor subtype distribution under different pathologic conditions and different patient populations will play a crucial role in the evaluation of these potentially therapeutic drugs.
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PMID:Endothelin-1 and endothelin receptor antagonists as potential cardiovascular therapeutic agents. 1179 30

Endothelin (ET)-1 causes vasoconstriction via ET(A) and ET(B) receptors located on vascular smooth muscle cells and vasodilatation via ET(B) receptors on endothelial cells. Studies in vitro indicate an upregulation of ET(B) receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ET(B) receptor antagonist BQ788 evoked a significant increase in FBF (31+/-13%) in the patients, whereas a 20+/-9% reduction was observed in the control subjects. The ET(A) receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102+/-25%) in the patients compared with no effect in the control subjects (-3+/-9%, P<0.001 versus patients). The ET(A) receptor antagonist BQ123 increased FBF to a similar degree in patients (39+/-11%) as in control subjects (41+/-11%). The increase in FBF evoked by selective ET(A) receptor blockade was significantly (P<0.05) less than that evoked by combined ET(A)/ET(B) receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1-mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ET(B)-mediated vasoconstriction.
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PMID:Combined endothelin receptor blockade evokes enhanced vasodilatation in patients with atherosclerosis. 1195 Jul 9

To investigate the molecular mechanisms responsible for the regional selectivity of early atherogenesis, we have applied a non-uniform shear stress to cultured human umbilical vein endothelial cells (HUVEC). We used a microcarrier culture system and a combination of subtraction and reverse-subtraction methods to isolate a number of genes upregulated by shear stress. The resultant subtracted library includes several known genes (e.g. MCP-1, TM) whose responsiveness to shear stress has been previously reported, indicating that the library is enriched for genes upregulated by shear stress. Also included are atherosclerosis-related genes (e.g. CTGF, IL-8) whose responsiveness to shear stress had not been demonstrated, other known genes whose relationship to atherosclerosis had not been reported, and novel genes. Some responsive to centrifugal force and shear stress (RECS) genes are also upregulated following stimulation by steady laminar shear stress in a parallel plate chamber. Interestingly, the library includes ET-1 and PAI, which are well known atherogenic factors that are downregulated by laminar shear stress. This implies that turbulent shear stress has effects on HUVEC that are different from those elicited by laminar shear stress. Importantly, analysis of specimens taken from human aorta showed that several RECS genes are transcriptionally upregulated in atherosclerotic lesions, suggesting that the subtracted library includes novel therapeutic targets for the treatment of atherosclerosis.
Atherosclerosis 2002 Jun
PMID:Large scale isolation of non-uniform shear stress-responsive genes from cultured human endothelial cells through the preparation of a subtracted cDNA library. 1199 52


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