UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular calcification (VC) is an orchestrated event, evoking the programmed process of the osteogenesis and triggered by inflammatory cytokines active at vascular level. VC is a dynamic process in which the vessel wall intima, media and also cardiac valves may be involved. Intimal calcification is an endochondral ossification process in which type II collagen is mineralized by calcium deposition. In contrast, an intra-membranous ossification process leads to medial calcification, while a dystrophic calcification process is responsible for valvular calcification. Mechanisms involved in VC may be summarized as: 1. Activation of osteogenesis in the vessel wall, 2. Loss of inhibitory factors, 3. Enhanced bone turnover, and 4. Abnormalities in mineral metabolism. The signaling axis constituted by osteoprotegerin (OPG), receptor activator nuclear factor kB (RANK) and its ligand (RANKL), along with the monocyte colony stimulating factor (M-CSF) and the transcription factor core Binding protein (Cbfa-1), play a pivotal role in the control of VC. In contrast, fetuin-A, matrix G1a protein (MGP) and osteopontin (OPN) control the inhibition of VC. In addition, abnormal mineral metabolism with enhanced phosphates availability favors calcium deposition. The inflammatory cytokines interleukin (IL-1) and tumor necrosis factor (TNF)-alpha enhance OPG and RANKL function in the vessel wall leading to VC. VC is a controlled process, depending on the balance between osteoblastic and osteoclastic influences and further modulated by the influence of risk factors like diabetes, smoking, age, hypertension and dyslipidemia. Recent advances in diagnostic tools such as with multi-detector computed tomography (MDCT) and electron beam computed tomography (EBCT), may help diagnosis and delineation of VC in the clinical setting and aid in understanding its prognostic value.
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PMID:Molecular determinants of vascular calcification: a bench to bedside view. 1691 72

The pathophysiological consequences of excess mineralocorticoid for salt status include hypertension, vascular inflammation, and cardiac fibrosis. Mineralocorticoid receptor (MR) blockade can both prevent and reverse established inflammation and fibrosis due to exogenous mineralocorticoids or endogenous glucocorticoid activation of the MR. Glucocorticoids also exert potent antiinflammatory effects via glucocorticoid receptors (GR) in the vascular wall. We propose that GR signaling may ameliorate mineralocorticoid/salt-induced vascular inflammation and fibrosis in the mineralocorticoid/salt model. In the present study, the role of GR in the mineralocorticoid/salt model was explored in uninephrectomized rats that were maintained on 0.9% saline solution to drink and treated as follows: control (CON), no further treatment; deoxycorticosterone (DOC; 20 mg/wk) for 4 wk (DOC4); DOC for 8 wk (DOC8); DOC for 8 wk plus the GR antagonist RU486 (2 mg/d) wk 5-8 (DOC8/RU486); and DOC for 8 wk plus RU486 and the MR antagonist eplerenone (EPL; 50 mg/kg.d) for wk 5-8 (DOC8/RU486+EPL). DOC treatment significantly increased systolic blood pressure, cardiac fibrosis, inflammation (ED-1-positive macrophages and osteopontin), and mRNA for markers of oxidative stress (p22phox, gp91phox, and NAD(P)H-4). GR blockade reduced the DOC-mediated increase in systolic blood pressure and the number of infiltrating ED-1-positive macrophages but had no effect on fibrosis, oxidative stress, or osteopontin mRNA levels. EPL reversed DOC-induced pathology in the absence or presence of GR blockade. Thus, blocking agonist activity at the GR neither enhances nor attenuates the fibrotic response, although it may modulate systolic blood pressure and macrophage recruitment in the mineralocorticoid/salt model.
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PMID:The role of the glucocorticoid receptor in mineralocorticoid/salt-mediated cardiac fibrosis. 1699 Mar 42

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties.
Hypertension 2006 Nov
PMID:Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats. 1700 Sep 33

Nitric oxide (NO) depletion in rats induces severe endothelial dysfunction within 4 days. Subsequently, hypertension and renal injury develop, which are ameliorated by alpha-tocopherol (VitE) cotreatment. The hypothesis of the present study was that NO synthase (NOS) inhibition induces a renal cortical antioxidative transcriptional response and invokes pro-oxidative and proinflammatory gene expression due to elimination of dampening effects of NO and enhanced oxidative stress. Male Sprague-Dawley rats received NOS inhibitor N(omega)-nitro-l-arginine (l-NNA, 500 mg/l water) for 4 (4d-LNNA), 21 (21d-LNNA), or 21 days with VitE in chow (0.7 g/kg body wt/day). Renal cortical RNA was applied to oligonucleotide rat arrays. In 4d-LNNA, 21d-LNNA, and 21d-LNNA+VitE, 120, 320, and 184 genes were differentially expressed, respectively. Genes related to glutathione and bilirubin synthesis were suppressed during 4d and 21d-LNNA and not corrected by VitE. Proteinuria, tubulointerstitial macrophages, and heme-oxygenase-1 (HO-1) expression were strongly correlated. Remarkably, pro-oxidative genes were not induced. Inflammation- and injury-related genes, including kidney injury molecule-1 and osteopontin, were unchanged at day 4, induced at 21d, and partly corrected by VitE. Superimposing HO-1 inhibition on NOS inhibition had no impact on the development of hypertension. To summarize, renal expression of genes involved in synthesis of the antioxidants glutathione and bilirubin seemed directly NO dependent, but there were no direct effects of NO depletion on pro-oxidant systems. This indicates that renal transcriptional regulation of two defense systems, glutathione and bilirubin syntheses, seems to depend upon adequate NO synthesis. Interaction between NO synthesis and heme degradation pathways for blood pressure regulation was not found.
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PMID:Transcriptome-based identification of pro- and antioxidative gene expression in kidney cortex of nitric oxide-depleted rats. 1704 89

Qin-Dan-Jiang-Ya-Tang (QDJYT) is a traditional Chinese herbal medicine for the treatment of hypertension. The effect of QDJYT on blood pressure and on vascular remodeling in hypertension was investigated in the model of spontaneous hypertensive rats (SHR). Sixteen SHRs were divided into two groups, the SHR group and the SHR+QDJYT group. Eight WKY rats were a normal control group. QDJYT (750 mg/kg) was orally administered daily for 12 weeks in SHR+QDJYT group. After 12 weeks, thoracic aortas were segregated. Media thickness (MT), lumen diameter (LD), the ratio of MT to LD, the volume fraction of collagen (VFC) in media, the ultrastructure of vascular smooth muscle cells (VSMCs) and the expression of osteopontin (OPN) mRNA were examined by histological staining, transmission electron microscope (TEM), and real-time PCR, respectively. It was observed in our study that MT, MT/LD, VFC and the expression of OPN mRNA were higher in the SHRs than in the WKY rats, volume and numeral density of mitochondria in vascular smooth muscle cells (VSMCs) in media increased obviously. However, in the SHRs treated with QDJYT, we found MT, MT/LD, VFC and the expression of OPN gene were lower than in the SHRs, and the phenotype of VSMCs were close to normal. These results suggest that QDJYT could reverse the vascular remodeling in SHR, and the mechanisms may be related to the suppressive effect of QDJYT on the expression of OPN mRNA in arterial wall.
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PMID:Effect of traditional Chinese medicine Qin-Dan-Jiang-Ya-Tang on remodeled vascular phenotype and osteopontin in spontaneous hypertensive rats. 1711 65

The assessment of target organ damage is important in defining the optimal treatment of hypertension and blood pressure-related cardiovascular disease. The aims of the present study were (1) to investigate candidate biomarkers of target organ damage, osteopontin (OPN) and plasminogen activator inhibitor-1 (PAI-1), in models of malignant hypertension with well characterized end-organ pathology; and (2) to evaluate the effects of chronic treatment with a p38 MAPK inhibitor. Gene expression, plasma concentrations, and renal immunohistochemical localization of OPN and PAI-1 were measured in stroke-prone spontaneously hypertensive rats on a salt-fat diet (SFD SHR-SP) and in spontaneously hypertensive rats receiving N(omega)-nitro-L-arginine methyl ester (L-NAME SHR). Plasma concentrations of OPN and PAI-1 increased significantly in SFD SHR-SP and L-NAME SHR as compared with controls, (2.5-4.5-fold for OPN and 2.0-9.0-fold for PAI-1). The plasma levels of OPN and PAI-1 were significantly correlated with the urinary excretion of albumin (p < 0.0001). Elevations in urinary albumin, plasma OPN and PAI-1 were abolished by chronic treatment (4-8 weeks) with a specific p38 MAPK inhibitor, SB-239063AN. OPN immunoreactivity was localized predominantly in the apical portion of tubule epithelium, while PAI-1 immunoreactivity was robust in glomeruli, tubules and renal artery endothelium. Treatment with the p38 MAPK inhibitor significantly reduced OPN and PAI-1 protein expression in target organs. Kidney gene expression was increased for OPN (4.9- and 7.9-fold) and PAI-1 (2.8- and 11.5-fold) in SFD SHR-SP and L-NAME SHR, respectively. In-silico pathway analysis revealed that activation of p38 MAPK was linked to OPN and PAI-1 via SPI, c-fos and c-jun; suggesting that these pathways may play an important role in p38 MAPK-dependent hypertensive renal dysfunction. The results suggest that enhanced OPN and PAI-1 expression reflects end-organ damage in hypertension and that suppression correlates with end-organ protection regardless of overt antihypertensive action.
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PMID:P38 MAPK inhibitors suppress biomarkers of hypertension end-organ damage, osteopontin and plasminogen activator inhibitor-1. 1743 56

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ERalpha and ERbeta. Therefore, we determined whether selective activation of ERalpha or of ERbeta would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt-treated rats. The ERalpha agonist 16alpha-LE2, the ERbeta agonist 8beta-VE2, and the nonselective estrogen receptor agonist 17beta-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16alpha-LE2 and 17beta-estradiol but not by 8beta-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ERalpha or ERbeta protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ERbeta agonists such as 8beta-VE2 have a therapeutic potential in the treatment of hypertensive heart disease.
Hypertension 2007 Aug
PMID:Both estrogen receptor subtypes, alpha and beta, attenuate cardiovascular remodeling in aldosterone salt-treated rats. 1756 76

Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca(2+)/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.
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PMID:Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB. 1815 95

Osteopontin (OPN), a proinflammatory cytokine, plays an important role in renal fibrosis. We reported that plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. However, the regulatory mechanism of OPN by aldosterone remains unclear. Here, we report the transcriptional regulation of OPN expression by aldosterone and the functional effects of aldosterone-mediated OPN transcription in renal fibroblasts. Aldosterone induced OPN expression in a dose-dependent manner with significant responses at 10 nmol/L (1.6+/-0.2-fold of controls, P<0.05, n=5) and elicited maximal effects at 10 micromol/L (3.5+/-0.4-fold of controls, P<0.01, n=5). Aldosterone increased OPN expression in a time-dependent manner with a maximal effect after 48 hours (2.7+/-0.3-fold of controls, P<0.01, n=5). This effect was abolished by the mineralocorticoid receptor (MR) antagonist spironolactone. Luciferase promoter deletion assays identified a novel cis regulatory element (-2153 to -1758) in the OPN promoter that is responsive to aldosterone. This element contains an activator protein-1 (AP-1) and nuclear factor kappa B (NF kappaB) site. Electrophoretic mobility shift assays, supershift assays, and chromatin immunoprecipitation assays identified both AP-1 and NF kappaB as the DNA binding proteins induced by aldosterone with spironolactone inhibiting aldosterone-induced AP-1 or NF kappaB activity. OPN-siRNA inhibited completely the induction of cell proliferation, type I, III, and IV collagen synthesis by aldosterone. These results indicate that aldosterone induced MR-mediated OPN expression through AP-1 and NF kappaB activation and suggest that aldosterone plays an important role in renal fibrosis through the induction of OPN.
Hypertension 2008 Feb
PMID:Osteopontin in rat renal fibroblasts: functional properties and transcriptional regulation by aldosterone. 1815 41

Some antihypertensive agents may improve resistance artery remodeling in hypertensive patients whereas other agents may not, for similar blood pressure reduction. We questioned whether the selective mineralocorticoid receptor blocker eplerenone improves resistance artery remodeling in hypertensive patients versus the beta-blocker atenolol. Sixteen hypertensive patients were randomly assigned to double-blind daily treatment with eplerenone or atenolol. Resistance arteries from gluteal subcutaneous tissue were assessed on a pressurized myograph. After 1 year of treatment, systolic and diastolic blood pressures were similarly well controlled in both groups. Endothelial function did not change with treatment in either group. Media/lumen ratio and cross-sectional area were unchanged in either the atenolol or the eplerenone group. In atenolol-treated patients, the arterial wall became stiffer, whereas in the eplerenone-treated patients, it became less stiff and similar to that of a normotensive control group. The media collagen/elastin ratio was reduced only after eplerenone treatment. Circulating concentrations of osteopontin, monocyte chemoattractant protein-1, basic fibroblast growth factor, interleukin-8, and interleukin-10 were significantly reduced only by eplerenone. However, plasma interleukin-1 receptor a concentration was significantly reduced by both drugs. In conclusion, in hypertensive patients, blood pressure control for 1 year with atenolol was associated with increased wall stiffness of resistance arteries, whereas eplerenone treatment was associated with reduced stiffness, decreased collagen/elastin ratio, and a reduction in circulating inflammatory mediators. These data raise the possibility that eplerenone treatment of hypertensive patients when normalizing blood pressure could potentially be associated with better vascular protection and outcomes than the beta-blocker atenolol, which remains to be demonstrated.
Hypertension 2008 Feb
PMID:Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. 1819 60

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