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)

AA (arachidonic acid) hydroxylation to 20-HETE (20-hydroxyeicosatetraenoic acid) influences renal vascular and tubular function. To identify the CYP (cytochrome P450) isoforms catalysing this reaction in the mouse kidney, we analysed the substrate specificity of Cyp4a10, 4a12a, 4a12b and 4a14 and determined sex- and strain-specific expressions. All recombinant enzymes showed high lauric acid hydroxylase activities. Cyp4a12a and Cyp4a12b efficiently hydroxylated AA to 20-HETE with V(max) values of approx. 10 nmol x nmol(-1) x min(-1) and K(m) values of 20-40 microM. 20-Carboxyeicosatetraenoic acid occurred as a secondary metabolite. AA hydroxylase activities were approx. 25-75-fold lower with Cyp4a10 and not detectable with Cyp4a14. Cyp4a12a and Cyp4a12b also efficiently converted EPA (eicosapentaenoic acid) into 19/20-OH- and 17,18-epoxy-EPA. In male mice, renal microsomal AA hydroxylase activities ranged between approx. 100 (NMRI), 45-55 (FVB/N, 129 Sv/J and Balb/c) and 25 pmol x min(-1) x mg(-1) (C57BL/6). The activities correlated with differences in Cyp4a12a protein and mRNA levels. Treatment with 5alpha-dihydrotestosterone induced both 20-HETE production and Cyp4a12a expression more than 4-fold in male C57BL/6 mice. All female mice showed low AA hydroxylase activities (15-25 pmol x min(-1) x mg(-1)) and very low Cyp4a12a mRNA and protein levels, but high Cyp4a10 and Cyp4a14 expression. Renal Cyp4a12b mRNA expression was almost undetectable in both sexes of all strains. Thus Cyp4a12a is the predominant 20-HETE synthase in the mouse kidney. Cyp4a12a expression determines the sex- and strain-specific differences in 20-HETE generation and may explain sex and strain differences in the susceptibility to hypertension and target organ damage.
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PMID:Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. 1711 42

To determine risk factors of accelerated atherosclerosis in patients with systemic lupus erythematosus (SLE), 72 patients with inactive disease and 36 age- and sex-matched controls were included. The intima-media thickness (IMT) of the common carotid artery was determined by ultrasound. Traditional risk factors and disease-related factors were recorded. Cardiovascular risk was estimated using SCORE (systematic coronary risk evaluation). Markers of inflammation, endothelial activation and vascular remodelling (matrix metalloproteinases (MMP-3, MMP-9) and tissue inhibitor of metalloproteinase- 1 (TIMP- 1)) were determined. IMT was increased in patients (0.67 mm+/-0.13 versus 0.61 mm+/-0.11, P < 0.05). Prevalence of hypertension (33% versus 6%, P < 0.001), SCORE (2.2 (1.7-4.2) versus 1.7 (1.3-2.1), P < 0.001), as well as parameters of inflammation (CRP 1.8 (0.6-5.8) mg/L versus 0.6 (0.2-1.0) mg/L, P < 0.001) and endothelial activation (VCAM-1 505 (389-683) ng/mL versus 374 (322-427) ng/mL, P < 0.001) and von Willebrand factor (138 (59-208)% versus 48 (24-92)%, P < 0.001), were increased in patients. Vascular remodelling was altered: MMP-3 and TIMP-1 were increased (18 (10-29) ng/mL versus 8 (5-11) ng/mL, P < 0.001, and 275 (216-352) ng/mL versus 230 (197-268) ng/mL, P < 0.001, respectively), and MMP-9 was decreased in SLE (266 (147-412) ng/mL versus 348 (226-530) ng/mL, P < 0.05). Univariate analyses revealed that in patients IMT was associated with age, systolic blood pressure, SCORE and disease duration. In multivariate analysis, age and SCORE were independent predictors of IMT. In conclusion, SLE patients have an increased IMT, which is associated with traditional risk factors. Non-traditional risk factors, such as endothelial activation, altered vascular remodelling and disease duration, might play an additional role.
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PMID:Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. 1712 May 95

Matrix metalloproteinases (MMPs) have been implicated in the atherosclerotic process and risk factors for the disease such as hypertension, hyperlipidemia, or diabetes mellitus in adults. So far, circulating levels of MMPs and their tissue inhibitors (TIMPs) have not been assessed in children and adolescents with obesity, a known risk factor for cardiovascular disease. Plasma levels of MMP-9 and TIMP-1 were measured immunoenzymatically in 45 obese children and adolescents, aged 15 +/- 1.8 years. The control group consisted of 28 healthy children, aged 14.5 +/- 2.5 years. MMP-9 and TIMP-1 concentrations were higher in obese children than in the control group (MMP-9: 553.5 +/- 311 vs 400.4 +/- 204 ng/mL, respectively; P = .02; TIMP-1: 161.2 +/- 32 vs 143.1 +/- 20.1 ng/mL, respectively; P = .03). We found significantly higher levels of MMP-9 in obese children with coexisting hypertension than in obese normotensive patients (635 +/- 308 vs 450 +/- 289 ng/mL, respectively; P = .04). MMP-9 correlated with body mass index (BMI) (r = 0.33, P = .005) and fasting insulin (r = 0.3, P = .013); TIMP-1 correlated with BMI (r = 0.35, P = .006). In the group of obese hypertensive children (n = 25), MMP-9 correlated with BMI (r = 0.41, P = .001), systolic blood pressure (r = 0.41, P = .002), fasting insulin (r = 0.37, P = .006), and homeostasis model assessment index of insulin resistance (r = 0.27, P = .03). TIMP-1 correlated with BMI (r = 0.33, P = .025) and systolic (r = 0.38, P = .008) and diastolic (r = 0.47, P = .001) blood pressure. In the regression models, MMP-9 was found to be dependent on fasting insulin (R(2) = 0.16, P = .04), and TIMP-1 on BMI (R(2) = 0.14, P = .04). In the obese hypertensive group, TIMP-1 was dependent on diastolic blood pressure (R(2) = 0.18, P = .04). Obese children and adolescents have elevated plasma concentrations of MMP-9 and TIMP-1. Coexistence of hypertension may exacerbate alterations of extracellular matrix turnover in these patients. It might be hypothesized that elevated MMP and TIMP concentrations may be related to increased cardiovascular risk in obese and particularly in obese hypertensive children and adolescents.
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PMID:Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents. 1751 13

The human metabolic syndrome and its frequent sequela, type 2 diabetes are epidemic around the world. Alpha-linolenic acid (ALA, 18:3 n-3), eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) consumption ameliorates some of these epidemics' features thus leading one to question if consumption of EPA and DHA, and their metabolic precursor ALA reduce the conversion of metabolic syndrome to type 2 diabetes and reduce the major cause of death in the metabolic syndrome and type 2 diabetes-myocardial infarction. Contributing to myocardial infarction are metabolic syndrome's features of dyslipidemia (including elevated total cholesterol and LDL-c), oxidation, inflammation, hypertension, glucose intolerance, overweight and obesity. Inflammation, glucose and lipid levels are variously influenced by disturbances in various adipocytokines which are in turn positively impacted by n-3 polyunsaturated fatty acid consumption. Type 2 diabetes has all these features though elevated total cholesterol and LDL-c are rarer. It is concluded that EPA and DHA consumption significantly benefits metabolic syndrome and type 2 diabetes primarily in terms of dyslipidemia (particularly hypertriglyceridemia) and platelet aggregation with their impact on blood pressure, glucose control, inflammation and oxidation being less established. There is some evidence that EPA and/or DHA consumption, but no published evidence that ALA reduces conversion of metabolic syndrome to type 2 diabetes and reduces death rates due to metabolic syndrome and type 2 diabetes. ALA's only published significance appears to be platelet aggregation reduction in type 2 diabetes.
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PMID:The role of consumption of alpha-linolenic, eicosapentaenoic and docosahexaenoic acids in human metabolic syndrome and type 2 diabetes--a mini-review. 1789 98

The extracellular matrix is vital for maintaining tissue integrity, and the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system is involved in the regulation of extracellular matrix metabolism. Extracellular matrix turnover plays an important role in the change of large arterial mechanical properties in hypertension. However, the association of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) system and arterial stiffness is not straightforward and existing data are rather limited. Our objective is to explore the impact of the MMP-9/TIMP-1 system on large arterial stiffness in patients with essential hypertension. An automatic pulse wave velocity (PWV) measuring system was used to examine carotid-femoral PWV (CFPWV) and carotid-radial PWV (CRPWV) as the parameters reflecting central elastic large arterial and peripheral muscular medium-sized arterial elasticity, respectively; and serum MMP-9 and TIMP-1 levels, along with a number of other established biomarkers, were measured by enzyme-linked immunosorbent assay (ELISA) in 202 essential hypertensive patients and 54 age and gender-matched control subjects. Compared with the control subjects, hypertensive patients exhibited higher levels of MMP-9 (p=0.001) and TIMP-1 (p=0.002). Spearman's correlation analysis showed that serum levels of MMP-9 (p=0.014) and TIMP-1 (p=0.005) were significantly and positively correlated with CFPWV in hypertensive patients. A stepwise multiple regressive analysis demonstrated that age, systolic blood pressure, heart rate and TIMP-1 were independent predictors of CFPWV in patients with essential hypertension (adjusted r2=0.458). In conclusion, our results imply that the MMP-9/TIMP-1 system may play an important role in the determination of arterial function, and these findings may have implications for the involvement of MMP-9/TIMP-1 system in the pathophysiology of cardiovascular disease.
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PMID:Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. 1804 28

1. Plasma levels of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are potential markers of many diseases involving extracellular matrix remodelling such as hypertension. Our aim was to determine whether the anticoagulant used to collect plasma and several freeze-thaw cycles may influence the accuracy of plasma MMP and TIMP determinations. 2. Plasma samples of 18 healthy volunteers were collected on three anticoagulants: heparinate, citrate and EDTA. For each anticoagulant, we compared: (i) MMP-2 and MMP-9 levels using gelatin zymography and TIMP-1 and TIMP-2 concentrations using enzyme-linked immunosorbent assay; (ii) intra- and interassay coefficients of variation (CV); and (iii) MMP and TIMP levels after up to five freeze-thaw cycles. 3. The choice of anticoagulant influenced TIMP-2 and TIMP-1 concentrations (TIMP-2, P < 0.0001; paired comparisons, citrate vs EDTA, P < 0.0001; EDTA vs heparin, P < 0.0001; citrate vs heparin, P < 0.0001; TIMP-1, P < 0.001; paired comparisons, citrate vs EDTA, P = 0.10; EDTA vs heparin, P < 0.01; citrate vs heparin, P < 0.0001), but not those of MMP. We observed a bias with heparinate for TIMP-2, TIMP-1 and MMP-9 determinations. The anticoagulant did not influence intra-assay or interassay CV. Performing freeze-thaw cycles led to alterations in the TIMP-1 plasma levels (P < 0.0001), regardless of the anticoagulant used, whereas MMP and TIMP-2 concentrations were not significantly affected. 4. Anticoagulant influences the measured levels of MMP and TIMP in plasma and should be systematically reported. However, it does not influence the reproducibility of the measurements. Repeated freeze-thaw cycles alter the measurement of TIMP-1 levels and should be avoided.
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PMID:Influence of blood sampling procedure on plasma concentrations of matrix metalloproteinases and their tissue inhibitors. 1830 42

The endothelium plays a key role in the development of atherogenesis and its inflammatory and proliferative status influences the progression of atherosclerosis. The aim of this study is to compare the effects of two beta blockers such as nebivolol and atenolol on gene expression in human umbilical vein endothelial cells (HUVECs) following an oxidant stimulus. HUVECs were incubated with nebivolol or atenolol (10 micromol/L) for 24 hours and oxidative stress was induced by the addition of oxidized (ox)-LDL. Ox-LDL upregulated adhesion molecules (ICAM-1, ICAM-2, ICAM-3, E-selectin, and P-selectin); proteins linked to inflammation (IL-6 and TNFalpha), thrombotic state (tissue factor, PAI-1 and uPA), hypertension such as endothelin-1 (ET-1), and vascular remodeling such as metalloproteinases (MMP-2, MMP-9) and protease inhibitor (TIMP-1). The exposure of HUVECs to nebivolol, but not to atenolol, reduced these genes upregulated by oxidative stress both in terms of protein and RNA expression. The known antioxidant properties of the third generation beta blocker nebivolol seem to account to the observed differences seen when compared to atenolol and support the specific potential protective role of this beta blocker on the expression of a number of genes involved in the initiation and progression of atherosclerosis.
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PMID:Effects of nebivolol on endothelial gene expression during oxidative stress in human umbilical vein endothelial cells. 1843 28

The left ventricle (LV) remodels with age and in response to pressure overload. While aging and pressure overload are superimposed in the clinical context, the structural and functional consequences of the individual processes are not well-understood. Accordingly, the objective of this study was to compare the effects of both early and late chronic hypertension on extracellular matrix (ECM) remodeling. The following groups of Dahl rats were studied: 1) young salt-resistant (control, n=6); 2) young salt-sensitive (early phase of chronic hypertension, n=6); 3) middle-aged salt-resistant (aging, n=5); and 4) middle-aged salt-sensitive (late phase of chronic hypertension, n=6). We measured LV mass (LVM) and body weight (BW) and immunoblotted a panel of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and ECM proteins. Total collagen increased, several MMPs decreased, and TIMP-1 increased in the early phase of hypertension, consistent with fibrosis. Active MMP-8 decreased from 8,010+/-81 U in young salt-resistant to 5,260+/-313 U in young salt-sensitive (p<0.05) rats. During the late phase, chronic hypertension decreased total collagen levels and increased MMP-8 and MMP-14 (all p<0.05). Based on good-fit modeling analysis, MMP-14 (45 kDa) correlated positively with changes in LVM/BW during the early phase. In conclusion, this is the first study to evaluate MMP levels during both early and late chronic phases of hypertension. Our results highlight that ECM remodeling in response to pressure overload is a dynamic process involving excessive ECM accumulation and degradation.
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PMID:Effects of early and late chronic pressure overload on extracellular matrix remodeling. 1871 51

The endothelins (ET) are the family of 21 amino acid endogenous peptides with potent vasoconstriction function. There are 3 isoforms of the endothelin protein (ET-1, ET-2 and ET-3) encoded by separate genes and exhibit distinct tissue distribution and function. Endothelin 1 is the significant isoform in humans. Endothelin 1 is the most abundant, best characterized isoform with truly pluripotent properties. Endothelin 1 is involved in physiological processes of vascular tone and mitogenesis, whereas under pathological conditions fibrosis, vascular hypertension and inflammation are induced. In human body there are 2 separate ET receptors, ET(A)R and ET(B)R belonging to the G-protein family which produce differing, sometimes opposite effects. Both receptors are differentially expressed by different cell types as well as in different disease entities, In fibroblast cell culture in vitro ET-1 through its receptors modulates cell proliferation, differentiation, contraction and migration. Endothelin 1 is implicated in extracellular matrix (ECM) components synthesis. The dual regulatory role of ET-1 consist on stimulation of collagen I and III synthesis and simultaneously on inhibition of MMP-1 expression through inhibition of tissue inhibitors of metalloproteinase: TIMP-1 and TIMP-3. Endothelin 1 promotes the differentiation of fibroblasts into myofibroblast's phenotype via elevated expression of procontractile proteins alpha-SMA, ezrin, paxillin and moesin. The elevated level of endogenous ET-1 expression cause deficient of myofibroblast apoptosis and increased ECM components deposition. Endothelin 1 is a potent vasoconstrictor, a potent mitogen for fibroblast and smooth muscle cells, a strong stimulant of matrix biosynthesis and is a survival factor for myofibroblasts. Endothelin 1 plays a key role in inflammatory disease and in the connective tissue fibrosis. Elevated level of ET-1, TGF-beta and their receptors has been reported in the pathogenesis of systemic sclerosis.
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PMID:[Characteristic of the endogenous peptides--endothelins and their role in the connective tissue fibrosis]. 1893 63

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are thought to be associated with coronary artery disease. The association of these markers with incident coronary artery disease has not been well described. Using a case-cohort design, we selected 216 individuals who had incident coronary artery disease (case group) and 225 individuals from a cohort random sample (comparison group) from participants enrolled in the Atherosclerosis Risk in Communities study. We measured plasma levels of MMP-1 and TIMP-1, traditional risk factors, and other markers of inflammation. We found no significant difference in TIMP-1 levels between the case group (827.8 +/- 23.8 ng/mL) and the comparison group (819.31 +/- 16.1 ng/mL) (P=0.77), and no significant difference in the frequency of MMP-1 levels that were dichotomized at the minimum detectable value of 1.7 ng/mL (P=0.49). In models adjusted for age, sex, race, body mass index, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, triglycerides, fibrinogen, von Willebrand factor, and white blood cell count, the hazard-rate ratio for incident coronary artery disease was 1.14 (95% confidence interval, 0.63-2.04; P=0.67) for individuals whose TIMP-1 levels were above, versus at or below the mean, and 1.17 (95% confidence interval, 0.63-2.19; P=0.62) for individuals whose MMP-1 levels were above 1.7 ng/mL. We conclude that TIMP-1 and MMP-1 levels in plasma were not predictive of incident coronary artery disease in a case-cohort random sample of the Atherosclerosis Risk in Communities study, a population study of asymptomatic middle-aged adults who had no prevalent atherosclerosis upon enrollment.
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PMID:Matrix metalloproteinase-1 and tissue inhibitors do not predict incident coronary artery disease in the atherosclerosis risk in communities (ARIC) study. 1915 30


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