Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the possible involvement of angiotensin II (AII) in the pathogenesis of microvascular changes in severe hypertension, we investigated the effects of angiotensin II type 1 (AT1) receptor antagonist and angiotensin-converting enzyme inhibitor (ACEI) on the expression of adhesion molecules of leukocytes and brain microvessels. Male stroke-prone spontaneously hypertensive rats (SHRSP) at 19 weeks of age were divided into three groups and age-matched Wistar-Kyoto rats (WKY) were used as the control group. AT1 receptor antagonist (TCV-116, 0.5 mg/kg/day) and ACEI (captopril, 20 mg/kg/day) were administered to SHRSP for 4 weeks. Mac-1 expression in leukocytes was investigated by flow cytometric analysis. For endothelial cells, we examined the expression of intercellular adhesion molecule-1 (ICAM-1), the AT1 receptor, and glucose transporter-1 (GLUT-1, a marker of the blood-brain barrier) using reverse transcription-polymerase chain reaction (RT-PCR). The blood pressure of AT1 receptor antagonist and ACEI-treated groups was slightly lower than that of the control, but was still greater than 220 mm Hg. Mac-1 expression, as well as ICAM-1 expression, was higher in control SHRSP than in WKY. Such enhanced expression of adhesion molecules in SHRSP was ameliorated by the administration of AT1 receptor antagonist or ACEI, the former being more effective. AT1 receptor expression was higher in control SHRSP than in WKY, and was lower in the AT1 receptor antagonist group, whereas no difference was found in the ACEI group. No significant differences were found in GLUT-1 expression among all groups. In the case of hypertensive cerebral injuries in SHRSP, leukocytes may have an important role for initiation via adhesion to endothelial cells. AT1 receptor antagonist showed a beneficial effect for the amelioration of enhanced expression of adhesion molecule in both leukocytes and endothelial cells. Thus, AII seems to be an important mediator for the hypertensive microvascular injuries.
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PMID:Effects of the AT1 receptor antagonist on adhesion molecule expression in leukocytes and brain microvessels of stroke-prone spontaneously hypertensive rats. 1107 85

Angiotensin (Ang) II is considered a regulatory hormone stimulating vascular smooth muscle cell constriction, aldosterone release from the adrenal gland, and sodium reabsorption in the renal tubule. Furthermore, Ang II may be formed and act locally as a chemokine, inducing tyrosine phosphorylation, cell growth, hypertrophy, and differentiation. In addition, evidence has recently accrued showing that Ang II is important in stimulating the production of reactive oxygen species and the activation of ancient inflammatory mechanisms. The transcription factor nuclear factor kappa-B is pivotal to these processes. Nuclear factor kappa-B activation stimulates the expression of a gene menagerie important to chemoattraction, surface adhesion molecule expression, coagulation, and inflammation. Anti-inflammatory interventions may have therapeutic utility.
Hypertension 2001 Feb
PMID:Workshop: mechanisms and cardiovascular damage in hypertension. 1123 Mar 40

Platelets are formed from, and their function determined by, bone marrow megakaryocytes (MK). Previous studies have found that hypertension is associated with accentuated platelet function and that some antihypertensive drug classes have antiplatelet activity. We measured MK ploidy (DNA content), size, granularity, and expression of the adhesion molecule glycoprotein (GP) IIIa, using flow cytometry and measures of platelet function, in 12 untreated hypertensive patients and 14 normotensive subjects. Eight hypertensive patients were then treated with losartan (50 mg daily), an angiotensin receptor antagonist that lowers blood pressure, and MK and platelet parameters re-measured after 6 weeks. Hypertensive patients had, as compared with matched normotensive subjects: increased MK ploidy (mean +/- SD) 22.9 +/- 2.2 N versus 20.8 +/- 1.6 N (2P = 0.009); increased platelet size, 10.67 +/- 1.03fl versus 9.26 +/- 0.72fl (2P < 0.001); increased platelet expression of GP IIIa, 108.6 +/- 22.5 versus 92.0 +/- 12.3 (2P = 0.036); and reduced platelet count, (207 +/- 52) x 10(9)/l versus (257 +/- 55) x 10(9)/l (2P = 0.026). Losartan significantly reduced MK ploidy, 22.6 +/- 2.2 N versus 21.4 +/- 1.9 N (2P = 0.006); MK size, 607 +/- 22 versus 579 +/- 16 (2P = 0.003); and lengthened cutaneous bleeding time, 424 +/- 86s versus 563 +/- 164s (2P = 0.011), in hypertensive patients. Losartan did not alter MK granularity or GP IIIa expression, or platelet count, size, mass, GP IIIa expression, or aggregation. The data suggest that platelet changes in hypertension may be secondary to changes in MKs, and that anti-hypertensive treatment can alter MKs and the function of platelets they produce. Since antihypertensive therapy reduces the risk of stroke and myocardial infarction, MKs are a novel therapeutic target for the prevention of vascular events.
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PMID:Prothrombotic megakaryocyte and platelet changes in hypertension are reversed following treatment: a pilot study. 1130 15

Background: Several reports have shown that circulating, soluble cellular adhesion molecules and endothelin-1 (ET-1) are implicated in the pathophysiological events of atherosclerosis and may reflect the endothelial dysfunction characterizing this disorder. Methods: To evaluate the expression of these factors in arterial hypertension (AH), we measured plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble P-selectin (sP-selectin), and ET-1 in 60 untreated patients with mild to moderate AH (hypercholesterolemic: n=31, normocholesterolemic: n=29) and 30 sex- and age-matched normocholesterolemic normotensive controls. Results: Hypertensive patients exhibited significantly higher levels of sICAM-1 (234+/-21 vs. 187+/-12 ng/ml, P<0.005), sVCAM-1 (681+/-42 vs. 589+/-23 ng/ml, P<0.005), sP-selectin (89+/-17 vs. 55+/-11 ng/ml, P<0.01) and ET-1 (6.2+/-0.7 vs. 2.4+/-0.3 pg/ml, P<0.01) than did normotensive controls. The normocholesterolemic hypertensives had lower levels of sICAM-1, sVCAM-1 (P<0.01), sP-selectin and ET-1 (P<0.05) than hypercholesterolemic hypertensives, but higher levels than normotensive controls (P<0.05). In hypertensives, plasma ET-1 was significantly correlated with mean arterial pressure (r=0.51, P<0.03) and sICAM-1 levels (r=0.64, P<0.01). In hypercholesterolemic hypertensives, LDL cholesterol was also significantly correlated with plasma levels of sICAM-1 (r=0.53, P<0.04) and sP-selectin (r=0.41, P<0.05). Conclusions: Plasma levels of soluble cellular adhesion molecules are elevated in hypertensive patients in comparison to normotensive controls and may be related to plasma ET-1 activity. The coexistence of hypercholesterolemia may enhance the plasma soluble adhesion molecule activity induced by AH.
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PMID:Plasma levels of soluble cellular adhesion molecules in patients with arterial hypertension. Correlations with plasma endothelin-1. 1139 98

Several studies support the association between postprandially elevated triglyceride levels and atherosclerosis. Histological and cell culture investigations revealed, that triglyceride rich postprandial lipoproteins are taken up by macrophages and smooth muscle cells and are detectable as part of foam cells in vascular lesions. Remnant particles, generated by lipolysis of postprandial lipoproteins in vitro and fatty acids increase the permeability of the endothelium and are cytotoxic for endothelial cells. Besides these morphological changes of cells, lipoproteins have been shown to exert effects on cellular functions like the expression of membrane proteins and the production or release of several bioactive substances regulating communication with blood cells and other cell systems of the vascular wall, blood pressure and hemostasis. This review concentrates on the influence of postprandial lipoproteins on factors involved in the interaction of endothelial cells with blood leukocytes and factors mediating blood pressure regulation. Increased expression of adhesion molecules has been detected immunehistochemically in atherosclerotic plaques in animals and humans. It was demonstrated that patients with elevated triglyceride levels have increased levels of soluble adhesion molecules. Furthermore, postprandial lipoproteins were shown to induce membrane expression of adhesion molecules. This effect seems to be at least in part mediated by the oxidative modification of the particles. Accordingly chylomicrons separated after ingestion of safflower oil, rich in polyunsaturated linoleic acid, induced higher adhesion molecule expression at higher oxidant concentration compared with chylomicrons separated after ingestion of olive oil, rich in monounsaturated oleic acid. Several authors described effects of fatty acids on the expression of adhesion molecules. On the one hand, they may exert stimulatory effects as such, on the other hand cytokine induced adhesion molecule expression may be enhanced by certain fatty acids and inhibited by others, implying an interference with signal transduction processes. Effects of lipoproteins on vasoactive substances seem to be implicated in endothelial dysfunction, too. The endothelium-derived relaxing factor nitric oxide (NO) has gained increasingly attention in the last two decades and is regarded as protective against hypertension and atherosclerosis. It was demonstrated that chylomicrons and their remnants inhibited endothelium-dependent relaxations in isolated aortas. Vasodilatatory responses and nitric oxide metabolism were shown to be affected by the amount and composition of dietary fat. Cell culture experiments revealed modulation of NO release by certain fatty acids. Plasma levels of endothelin-1, a strong vasoconstrictor, have been shown to be increased in patients with type 2 diabetes and metabolic syndrome, respectively. Postprandially elevated triglycerides increased endothelin-levels in addition to insulin in patients with metabolic syndrome. In summary, there is evidence that the association between postprandial triglycerides and the metabolic syndrome is driven by direct influences on endothelial functions because plasma triglyceride levels are associated with levels of humoral risk markers of endothelial origin, and postprandial lipoproteins stimulate the release and/or expression of endothelial mediators in vitro, which induce atherogenesis and hypertension.
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PMID:Postprandial triglycerides and endothelial function. 1145 41

The use of viral vectors for vascular gene therapy targeted at the endothelium is limited by the promiscuous tropism of vectors and nonspecificity of viral promoters, resulting in high-level transgene expression in multiple tissues. To evaluate suitable endothelial cell (EC)-specific promoters for vascular gene therapy, we directly compared the ability of the fms-like tyrosine kinase-1 (FLT-1), intercellular adhesion molecule-2 (ICAM-2), and von Willebrand factor (vWF) promoters to drive EC-restricted transcription after cloning into adenoviral vectors upstream of lacZ. Vastly different expression profiles were observed. Whereas both FLT-1 and ICAM-2 promoters generated transgene expression levels similar to cytomegalovirus in ECs in vitro, vWF expression levels were extremely low. Analysis of non-EC types revealed that ICAM-2 but not FLT-1 evoked leaky transgene expression, thus identifying FLT-1 as the most selective promoter. With an ex vivo human gene therapy model, the FLT-1 promoter demonstrated EC-specific transgene expression in intact human vein but no detectable expression from infected exposed smooth muscle cells in EC-denuded vein. Furthermore, when adenoviruses were systemically administered to mice, the FLT-1 promoter demonstrated extremely low-level gene expression in the liver, the major target organ for adenoviral transduction in vivo. This study highlights the potential of using the FLT-1 promoter for local and systemic human gene therapy in hypertension and its complications.
Hypertension 2001 Jul
PMID:Analysis of cell-specific promoters for viral gene therapy targeted at the vascular endothelium. 1146 61

Hypercholesterolaemia is associated with accentuated platelet function. We assessed in a pilot study whether megakaryocytes (MK), the platelet precursor cell, were altered in subjects with primary hypercholesterolaemia and whether these changes were linked with platelet function. MK and platelet function were assessed in eight untreated patients with primary hypercholesterolaemia (total cholesterol, TC > 7 mmol/l), and 14 control subjects (TC < or = 7 mmol/l): MK ploidy (DNA content), size, granularity, and expression of the adhesion molecule GP IIIa, and platelet expression of GP IIIa, P selectin and CD 63, and RNA content, were each measured using flow cytometry; mean platelet volume, platelet count, plasma thrombopoietin, and cutaneous bleeding time were also assessed. Hypercholesterolaemic patients had increased MK ploidy, mean (SD) 22.9 N (2.3) vs. 20.8 N (1.6) (2P=0.021); platelet size, 10.6 fl (1.2) vs. 9.3 fl (0.7) (2P=0.006); and platelet expression of GP IIIa, 111.3 (18.9) vs. 92.0 (12.3) (2P=0.010), as compared with matched control subjects. Cutaneous bleeding time tended to be reduced in the hypercholesterolaemic patients, 364 s (136) vs. 483 s (165) (2P=0.11). No differences in MK size, granularity or GP IIIa expression, or platelet count, mass, RNA content, P selectin or CD 63 expression, or plasma thrombopoietin were seen. The data suggest that aspects of megakaryocytes and platelets are altered in hypercholesterolaemia, as has also been seen in other vascular risk factors states, including hypertension and diabetes mellitus. Furthermore, changes in megakaryocytes may have contributed to the altered platelet function seen here. Further study is now required to assess whether lipid lowering therapy "normalises" these changes in the megakaryocyte-platelet haemostatic axis.
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PMID:Altered megakaryocyte-platelet haemostatic axis in hypercholesterolaemia. 1148 81

Progression of atherosclerosis is currently believed to involve interactions between leukocytes and vascular endothelium. Epidemiological risk factors for atherosclerosis such as hypertension and smoking are known to cause endothelial dysfunction, which is an early event in the atherosclerotic process; they also may be considered in the light of their effects on adhesion molecule expression and release. Little is known about the additive effect between these two risk factors on endothelial adhesion molecule expression and nitric oxide release. Soluble adhesion molecules and the nitric oxide were quantified in smoking hypertensive patients in comparison to those from patients with hypertension alone. Cotinine, a stable metabolite of nicotine, has been used to identify smokers. One hundred and three hypertensive patients were selected: 51 smokers (plasma cotinine levels >25 ng/ml) and 52 non-smokers. Plasma concentrations of soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble endothelial leukocyte adhesion molecule-1 (sELAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-I) were quantified with ELISA methods. Plasma concentration of nitric oxide metabolites was measured by HPLC, whilst plasma concentration of cotinine was measured by RIA. Significant increases of sICAM-1 and sVCAM-1 were demonstrated in smokers (p<0.001 and p<0.05, respectively). In the same patients, a positive significant correlation between sVCAM-1 and plasma cotinine levels was observed (p<0.002). Nitric oxide metabolites were reduced significantly (p<0.04) in smokers. In conclusion, our data show that the two risk factors, smoking and hypertension, are additive risk factors in generating endothelial dysfunction and vascular damage, which plays a key role in atherogenesis.
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PMID:Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. 1160 80

There is compelling evidence for endothelial dysfunction in both type 1 and type 2 diabetics. This dysfunction is manifest as blunting of the biologic effect of a potent endothelium-derived vasodilator, nitric oxide, and increased production of vasoconstrictors such as angiotensin II, ET-1, and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. These agents and other cytokines and growth factors whose production they stimulate cause acute increases in vascular tone, resulting in increases in blood pressure, and vascular and cardiac remodeling that contributes to the microvascular, macrovascular, and renal complications in diabetes. Reactive oxygen species, overproduced in diabetics, serve as signaling molecules that mediate many of the cellular biochemical reactions that result in these deleterious effects. Adverse vascular consequences associated with endothelial dysfunction in diabetes mellitus are Decreased nitric oxide formation, release, and action Increased formation of reactive oxygen species Decreased prostacyclin formation and release Increased formation of vasoconstrictor prostanoid Increased formation and release of ET-1 Increased lipid oxidation Increased cytokine and growth factor production Increased adhesion molecule expression Hypertension Changes in heart and vessel wall structure Acceleration of the atherosclerotic process Treatment with antioxidants and with inhibitors of the renin-angiotensin system may reverse some of the pathologic vascular changes associated with endothelial dysfunction.
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PMID:Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. 1172 7

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.
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PMID:Endothelial dysfunction in hypertension. 1181 68


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