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)

We investigated the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) on the inhibitory effects of an angiotensin II type-1 receptor (AT1) blocker on atherosclerosis and explored cellular mechanisms. We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition. Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration; however, both drugs decreased plaque area and lipid deposition after 10 weeks. We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day, respectively. At these doses, neither drug had an effect on atherosclerotic lesions. When both drugs were combined at these doses, a significant reduction in atherosclerotic lesions was observed. Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits p22phox and p47phox, production of superoxide anion, the expression of monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 expression were observed. These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade, particularly when given concomitantly, blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects.
Hypertension 2004 Nov
PMID:Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. 1545 25

Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor-alpha (TNF-alpha) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF-alpha rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 [2.04] to 2.94 [2.47] pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 [6.07] versus 2.12 [1.89]; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1beta (C-511T), IL-6 (G-174C), TNF-alpha (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.
Hypertension 2004 Nov
PMID:Short- and long-term changes in plasma inflammatory markers associated with preeclampsia. 1569 40

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
Hypertension 2005 Apr
PMID:Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. 1571 Jul 85

Interleukin-6 (IL-6), the major proinflammatory cytokine, has been described to be associated with the hypertensive and atherosclerotic states. We aimed to explore whether the concentration of circulating IL-6 and adhesion molecules could be modified by decreasing blood pressure in hypertensive subjects. A total of 30 subjects (18 men), aged 34-48 years, were enrolled in this study, 17 hypertensive never-treated patients (HTA) and 13 normotensive subjects (C). HTA subjects were treated with irbesartan, 150-300 mg/day for 3 months, and serum IL-6, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, sP-selectin, sE-selectin and monocyte chemoattractant protein-1 were measured at 0 and 12 weeks. The two study groups were similar in age, body mass index (BMI) and gender. At baseline, circulating IL-6 levels, but not adhesion molecules, were significantly associated with systolic blood pressure (r=0.41; P=0.03) and BMI (r=0.53; P=0.005). Systolic and diastolic blood pressure decreased significantly (P<0.01) in parallel to serum IL-6 levels (from 3.72+/-0.82 to 3.23+/-0.19 pg/ml, P=0.02) reaching a similar concentration to normotensive patients (3.33+/-0.3 pg/ml) after treatment with irbesartan. No significant changes were observed in any other of the tested parameters. In conclusion, the treatment of high blood pressure lowers circulating IL-6 in young hypertensive patients.
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PMID:Lowering of blood pressure leads to decreased circulating interleukin-6 in hypertensive subjects. 1575 24

Calcitonin gene-related peptide, a potent vasodilator neuropeptide, is localized in perivascular sensory nerves. We have reported that alpha-calcitonin gene-related peptide knockout mice have elevated baseline blood pressure and enhanced hypertension-induced renal damage compared with wild-type controls. Thus, the aim of this study was to determine the mechanism and functional significance of this increased hypertension-induced renal damage. We previously demonstrated by telemetric recording that the deoxycorticosterone-salt protocol produces a 35% increase in mean arterial pressure in both alpha-calcitonin gene-related peptide knockout and wild-type mice. Both strains of mice were studied at 0, 14, and 21 days after deoxycorticosterone-salt hypertension. Renal sections from hypertensive wild-type mice showed no pathological changes at any time point studied. However, on days 14 and 21, hypertensive knockout mice displayed progressive increases in glomerular proliferation, crescent formation, and tubular protein casts, as well as the inflammatory markers intercellular adhesion molecule-1, vascular adhesion molecule-1, and monocyte chemoattractant protein-1. There was a significant increase in 24-hour urinary isoprostane, a marker of oxidative stress-induced lipid peroxidation, levels at days 14 and 21 in the hypertensive knockout compared with hypertensive wild-type mice. Urinary microalbumin was significantly higher (2-fold) at day 21 and creatinine clearance was significantly decreased 4-fold in the hypertensive knockout compared with hypertensive wild-type mice. Therefore, in the absence of alpha-calcitonin gene-related peptide, deoxycorticosterone-salt hypertension induces enhanced oxidative stress, inflammation, and renal histopathologic damage, resulting in reduced renal function. Thus, sensory nerves, via alpha-calcitonin gene-related peptide, appear to be renoprotective against hypertension-induced damage.
Hypertension 2005 Jul
PMID:Role of calcitonin gene-related peptide in hypertension-induced renal damage. 1628 67

Atherosclerosis is by far the leading cause of mortality and morbidity in patients with end stage renal disease undergoing chronic hemodialysis (HD). Vascular endothelial cell adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) are involved in the pathogenesis of atherosclerosis. Their soluble forms (sICAM-1, sVCAM-1) are considered potential serum markers of endothelial activation and atherosclerosis. The aim of this study was to clarify the influence of the HD procedure on the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. We evaluated 35 clinically stable patients (18 males, 17 females, mean age 61 +/- 12) on chronic HD treatment. Diabetes mellitus coexisted in eight patients and arterial hypertension in 23 patients. Blood was drawn before, every hour during, and after a single HD session in each patient. Low-flux cuprophane dialyzers (GFS 12, Gambro, Lund, Sweden) were used in 22 and high-flux polysulfone dialyzers (Hemoflow F 60S, Fresenius, Oberursel, Germany) in 13 cases. At 30 min into the HD session (n=31, 20 low-flux HD, 11 high-flux HD) blood was drawn simultaneously from the entrance and the exit line of the dialyzer. From all these samples, serum concentrations of sICAM-1 and sVCAM-1 were determined by commercially available enzyme immunoassays (ELISA, R&D Systems, Minneapolis, USA). Results were corrected according to hemoconcentration, where appropriate. Plasma levels of sVCAM-1 were elevated in patients with end stage renal disease before the beginning of the dialysis session when compared to healthy controls (1449 +/- 497 ng/mL vs. 691 +/- 118 ng/mL). On the contrary, such an elevation was not found in the case of sICAM-1 (231 +/- 58.5 ng/mL vs. 236.4 +/- 96.8 ng/mL in healthy controls). These levels remained stable in all measurements throughout the dialysis procedure. Furthermore, serum sICAM-1 and sVCAM-1 levels remained unaltered after the passage of the dialyzer. The levels of sICAM-1 and sVCAM-1 were not influenced by the existence of diabetes mellitus, hypertension, or by the utilization of biocompatible, high flux dialyzers. Our study confirms that in chronic HD patients serum levels for sVCAM-1 are elevated. The levels of adhesion molecules are not affected by the HD procedure. These findings probably can be attributed to a decreased renal clearance or catabolism of sICAM-1 and sVCAM-1 and to the different sources of the two molecules. Neither coexisting diabetes mellitus nor arterial hypertension influences the circulating levels of these adhesion molecules. The functional role of sVCAM-1 and sICAM-1, the exact renal contribution to their metabolism, and their role as markers of atherosclerosis in chronic renal disease need further evaluation.
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PMID:Hemodialysis procedure does not affect the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. 1595 49

Many patients with hypertension, particularly elderly patients, take nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensive agents. However, few studies describe the effect of the association of antihypertensive agents with NSAIDs on inflammatory response in hypertension. To investigate this, spontaneously hypertensive rats (SHRs) were treated with either diclofenac alone or diclofenac combined with losartan (an AT1 angiotensin II antagonist). The leukocyte-endothelial interaction was then observed using intravital microscopy. Blood pressure of SHR (169.6+/-3.6) was increased by diclofenac (186.4+/-2.9), reduced by losartan (152.6+/-3.5), and reduced by the combination of the 2 (158.9+/-3.7). All the treatments tested reduced the number of rollers, adherent and migrated leukocytes, and the expression of endothelial intercellular adhesion molecule-1 and P-selectin. The association of losartan reduced the effect of diclofenac on leukocyte migration. Neither treatment tested increased the venular shear rate or modified the venular diameters, number of circulating leukocytes, and L-selectin expression on granulocytes. The reduction of CD11/CD18 expression induced by diclofenac alone was hindered by losartan. A pharmacokinetic interference between losartan and diclofenac was ruled out since no significant differences were observed in the plasma concentrations of each drug when they were associated. In conclusion, although diclofenac does not interfere with the losartan antihypertensive effect, losartan attenuates the effect of diclofenac has on leukocyte behavior and expression of adhesion molecules. Losartan has an antimigratory effect, reducing leukocyte migration by reducing ICAM-1 and P-selectin expression. Losartan may hinder the full expression of the antimigratory effect of diclofenac.
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PMID:Losartan attenuates the antimigratory effect of diclofenac in spontaneously hypertensive rats. 1604 31

The endothelial lectinlike, oxidatively (ox-) modified LDL receptor LOX-1 is a critical player in the pathogenesis of atherosclerosis and myocardial ischemia. Ox-LDL binding of LOX-1 results in the expression of various adhesion molecules, which attract monocytes to endothelial cells, an initial step in atherogenesis. We wished to examine the role of the ox-LDL/LOX-1 signaling pathway in fibroblasts, which naturally express low levels of LOX-1. Rat cardiac fibroblasts were transfected with either cytomegalovirus (CMV)-LOX-1wt (amino acids [aa] 1 to 273) or CMV-LOX-1(1-261) (an ox-LDL-binding negative mutant, aa 1 to 261) plasmid. Western blots showed that LOX-1 protein expression was increased significantly in cells transfected with CMV-LOX-1wt or CMV-LOX-1(1-261) plasmid (P<0.01 vs control). Fibroblasts transfected with CMV-LOX-1wt showed ox-LDL binding, whereas fibroblasts without transfection and those transfected with CMV-LOX-1(1-261) did not bind ox-LDL. Compared with untransfected cells, ox-LDL treatment (50 microg/mL, 24 hours) markedly induced the expression of the leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM)-1 as well as matrix metalloproteinase (MMP)-1 in cells transfected with CMV-LOX-1wt (P<0.05) but not in cells transfected with CMV-LOX-1(1-261). Concurrently, ox-LDL treatment enhanced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) (P<0.05 vs control) in CMV-LOX-1wt-transfected cells. These data suggest that in cardiac fibroblasts, ox-LDL binds to LOX-1 and activates p38 MAPK, followed by the expression of ICAM-1, VCAM-1, and MMP-1. Thus, fibroblasts transform into an endothelial phenotype on transfection with CMV-LOX-1wt and subsequent exposure to ox-LDL. This study provides a useful model system (plasmid-transfected fibroblasts) to study the molecular biology of LOX-1.
Hypertension 2005 Sep
PMID:Adhesion molecule expression in fibroblasts: alteration in fibroblast biology after transfection with LOX-1 plasmids. 1611 44

Systemic factors and blood flow velocity related to atherosclerosis have been examined mainly separately or by in vitro studies. The aim of our study was to investigate the association between local coronary blood flow (corrected TIMI frame count, CTFC) and systemic atherosclerosis-related inflammatory parameters such as soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (Il-6), high sensitivity C-reactive protein (hsCRP) and von Willebrand factor (vWF) in humans. We enrolled the following groups of ischemic heart disease (IHD) patients: patients with coronary stenosis and stable (CAD, n = 96) or unstable angina (ACS, n = 27), patients with documented myocardial ischemia and normal coronary angiogram (NEG, n = 68). Patient groups showed only marginal differences in CTFC or sICAM-1 levels. In contrast, when IHD patients were studied individually, general positive correlation was found between CTFC and sICAM-1 level (r = 0.33; in NEG r = 0.25; in CAD r = 0.37; in ACS r = 0.61), being the strongest in ACS. The relation was independent from age, gender, BMI, smoking, hypertension, diabetes, previous myocardial infarction, family history of IHD, medication, hsCRP, IL-6 and vWF levels. (odds ratio, OR = 6.4; CI 95%: 2.43-16.84; p < 0.05). Nevertheless, correlation between CTFC and IL-6, hsCRP, vWF levels was not found. These results indicate inverse correlation between coronary blood flow and adhesion molecule production independently from conventional cardiovascular risk factors and inflammatory markers.
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PMID:Inverse correlation between coronary blood flow velocity and sICAM-1 level observed in ischemic heart disease patients. 1629 92

This study was designed to examine the plasma levels of adiponectin as well as markers of inflammation and endothelial function in peripheral arterial occlusive disease (PAOD), and to investigate the pathophysiological significance of adiponectin in this disease. Eighty-eight subjects with (n=40) and without PAOD (n=48) were enrolled. Multiple regression analysis including age, sex, body mass index, hypertension, diabetes, triglycerides, high-density lipoprotein cholesterol, creatinine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecules-1 (sVCAM-1), von Willebrand factor, and high-sensitive C reactive protein (Hs-CRP) showed that adiponectin concentration was significantly lower in PAOD subjects (PAOD: 7.9+/-0.7 microg/mL versus without PAOD: 9.5+/-0.6 microg/mL, F=4.94, p<0.03). Furthermore, concentrations of adiponectin (F=8.5, p<0.01) as well as sICAM-1 (F=5.8, p<0.02), sVCAM-1 (F=5.9, p<0.02), and Hs-CRP (F=3.8, p=0.05) were independently associated with ankle-brachial index. In 27 subjects (10 with PAOD and 17 without PAOD), adiponectin levels in the femoral artery and saphenous vein were measured. A significant step-up of adiponectin from the artery to the vein was observed in subjects without PAOD (+13.0%, p<0.01), but not in subjects with PAOD (+0.4%, NS). Plasma adiponectin as well as Hs-CRP were followed before and after percutaneous transluminal angioplasty (PTA) in eight patients. Adiponectin showed a tendency to decrease after PTA (day 6, -30.6%), although Hs-CRP significantly increased. Adiponectin is decreased in patients with PAOD in proportion to the severity of the disease. Adiponectin concentration could be a marker of the existence of atherosclerosis, and measurement of its concentration may be helpful in assessment of the progress of atherosclerosis.
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PMID:Adiponectin and inflammatory markers in peripheral arterial occlusive disease. 1632 91


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