Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epidemiological studies have established that diabetes mellitus and hypertension are independent risk factors for atherosclerosis. One of the earliest abnormalities seen in atherogenesis is enhanced monocyte adherence to the endothelium. The mechanisms by which diabetes mellitus or hypertension enhances monocyte-endothelial cell interactions are incompletely characterized. It is not known whether there are additive interactions between these risk factors on endothelial adhesiveness for monocytes. Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were fed a normal or fructose-enriched diet. In some cases, animals were injected with streptozotocin (35 mg/kg body weight) to induce diabetes. After 2 weeks, plasma was drawn for biochemical measurements, and thoracic aortas were harvested, opened longitudinally, and exposed to fluorescently labeled mouse monocytoid cells (WEHI 78/24, 2 x 10(6)/mL) for 30 minutes on a rocking platform. Adherent cells were counted by epifluorescence microscopy. WEHI 78/24 binding to aortic segments from SHR animals was elevated compared with segments from WKYs. Fructose feeding alone had no effect on endothelial adhesiveness. When WKYs were made hyperglycemic by STZ injection, monocyte binding was 160% of the control value. Elevated monocyte binding was also observed in aortas derived from SHR animals injected with STZ, indicating an additive effect of hypertension and hyperglycemia. To determine whether alterations in oxidative state played a role in the endothelial adhesiveness, aortic segments were exposed to lucigenin (250 micromol/L) for measurement of superoxide anion. Aortic segments from SHR elaborated 120% more superoxide anion than did controls. Elevated free-radical production was also observed in aortas from diabetic WKYs. Furthermore, thoracic aortas derived from diabetic SHR animals elaborated more superoxide anion than did any of the other groups (374%, P<0.05). Immunohistochemical staining for monocyte chemotactic protein-1 demonstrated increased expression in aortas isolated from diabetic WKY and SHR compared with control vessels. These studies demonstrate that both diabetes and hypertension lead to increased monocyte adherence to the endothelium. This abnormality is associated with increased vascular superoxide production and monocyte chemotactic protein-1 expression. Furthermore, there appears to be an additive interaction between hyperglycemia and hypertension in their effects on endothelial adhesiveness and its determinants.
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PMID:Interaction of diabetes and hypertension on determinants of endothelial adhesiveness. 963 36

Antagonists of the renin-angiotensin system, such as angiotensin type 1 (AT(1)) receptor inhibitors and angiotensin-converting enzyme inhibitors, are becoming increasingly popular agents in treating patients with systemic hypertension and minimizing organ damage. In the present study, we compared the effects of eprosartan, an AT(1) receptor inhibitor, with the diuretic hydrochlorothiazide in a group of newly diagnosed hypertensive patients with multiple risk factors for atherosclerosis. The subjects were monitored and tested at 0 and 4 weeks to determine their individual effects on vascular and inflammatory markers. Although blood pressure reduction was comparable between the 2 agents, there were notable differences in their effects on markers of inflammation and oxidation. We observed a 28% reduction in neutrophil superoxide anion generating capacity, a 34% reduction in soluble monocyte chemotactic protein-1, and a 35% reduction in soluble vascular cell adhesion molecule with eprosartan therapy (all p <0.05 from the start of therapy). In addition, eprosartan showed further benefit in its ability to increase low-density lipoprotein oxidation lag time, suggesting an increased resistance to oxidation and/or modification of low-density lipoprotein. Although hydrochlorothiazide was effective in blood pressure reduction, there were no significant changes in any of the above parameters after 4 weeks of treatment. These findings suggest that eprosartan, an AT(1) receptor inhibitor, effectively reduces systemic blood pressure and, compared with hydrochlorothiazide, suggests additional benefits in the vasculature by inhibiting mechanisms of inflammation and oxidation.
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PMID:Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation). 1189 10

At least four independent studies in different clinical settings showed that angiotensin-converting enzyme inhibitors (ACE-Is) such as enalapril effectively decrease plasma levels of circulating adhesion molecules (cAMs). To examine whether this effect may be mediated by the decreased action of angiotensin, we compared the effects of enalapril with the direct angiotensin-II antagonist, losartan, on plasma levels of cAMs, and monocyte chemotactic protein-1 (MCP-1). In a randomized trial, we recruited 32 untreated patients (19 male, aged 59+/-13 years) with hypertension, who received either enalapril (mean dose 17 mg/day) or losartan (mean dose 77 mg/day) at equipotent doses. Enalapril decreased plasma levels of all cAMs after 8 weeks of treatment: cE-selectin levels decreased by 13% (P=0.007), intercellular adhesion molecule-1 (cICAM-1) by 15% (P=0.002) and vascular cell adhesion molecule-1 (cVCAM-1) by 19% (P=0.003). Similarly, enalapril decreased plasma levels of MCP-1 by 13% (P<0.001). Losartan did not significantly change cAM or MCP-1 plasma concentrations after 8 weeks of treatment: cE-selectin levels decreased by 3%, cICAM-1 by 5%, cVCAM-1 by 8%, whereas MCP-1 increased by 2% (all P=NS; not significant). The enalapril effect on percentage changes of cVCAM-1 was significantly different from losartan (P=0.0429). Eight weeks of antihypertensive treatment with enalapril but not losartan, significantly decreased plasma levels of cAMs and MCP-1 in hypertensive patients. The beneficial effects of ACE-Is on cAMs may have implications for atherogenesis and the reduction of cardiovascular events, which cannot be fully explained by their antihypertensive effects alone.
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PMID:Effects of enalapril and losartan on circulating adhesion molecules and monocyte chemotactic protein-1. 1214 3

Aldosterone is a mineralocorticoid hormone that plays an important role in regulating electrolyte balance and blood pressure and also participates in endothelial dysfunction. We evaluated the direct effect of aldosterone on human umbilical vein cells (HUVEC). Levels of eNOS phosphorylation by vascular endothelial growth factor were diminished, and the amount of NO produced in response to vascular endothelial growth factor measured as NO2+NO3 was significantly decreased in cells previously incubated with aldosterone. Incubation with aldosterone for 24 h dose-dependently increased Nox4 mRNA expression in HUVEC. Although NF-kappaB was not apparently activated by aldosterone, mRNA levels of vascular cell adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 in HUVEC were significantly increased after incubation with aldosterone. Thus, aldosterone directly causes the dysregulation of endothelial cell function, which may be partly responsible for high blood pressure and atherosclerosis.
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PMID:Aldosterone impairs vascular endothelial cell function. 1668 76

Chronic angiotensin (ANG) II infusions into rats lead to augmented intrarenal levels of ANG II and inflammatory factors, impaired renal function, and progressive hypertension. Residual effects persist after cessation of ANG II infusions, as manifested by a hypertensive response to high-salt intake. This study was performed to determine the residual cytokines and chemokines following the cessation of ANG II infusion. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups. Minipumps were removed on day 12 with subsequent harvesting of kidneys at 0, 3, and 6 days after cessation of ANG II infusion. After 12 days of ANG II infusion, systolic blood pressure, interstitial fibrosis, preglomerular hypertrophy, and interstitial macrophage infiltration were significantly enhanced compared with the shams. By 3 days following the cessation of ANG II infusion, systolic blood pressure was normalized; however, interstitial fibrosis and preglomerular hypertrophy were still present. Furthermore, increased interstitial macrophage infiltration was still present 6 days after cessation of ANG II infusion. Importantly, augmented mRNA levels of monocyte chemotactic protein (MCP)-1 (1.55 +/- 0.15 vs. 1.00 +/- 0.13, relative ratio) and transforming growth factor (TGF)-beta(1) (1.52 +/- 0.16 vs. 1.00 +/- 0.08) persisted 6 days after the withdrawal of ANG II infusion (1.60 +/- 0.20 for MCP-1 and 1.43 +/- 0.17 for TGF-beta(1)). Thus, the ANG II-induced activation of MCP-1 and TGF-beta(1) is sustained and may account for the persistent effect of chronic ANG II infusions on interstitial macrophage infiltration, suggesting a possible mechanism for the development of salt sensitivity in ANG II-dependent hypertension.
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PMID:Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. 1680 6

In a previous study, we performed a genome-wide quantitative trait loci (QTLs) analysis for blood pressure using F2 rats derived from Dahl salt-sensitive (DS) and Lewis (LEW) rats and identified two QTLs that influenced blood pressure levels. Although we determined that one of the causative genes in the chromosome (Ch) 1 region seemed to be Klk1, we did not perform detailed analyses on the Ch10 QTL region. The purpose of the present study was to identify candidate genes that influence blood pressure in the Ch10 QTL region. Using microarray analysis, we compiled a list of the genes that are differentially expressed between the two strains and that were localized to the Ch10 QTL region. Subsequent reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis identified that, while the expression levels of Ccl2 mRNA were not different between the kidneys of DS and LEW rats fed a normal diet, those in DS were 10-fold higher than those in LEW under a high-salt diet. Although the promoter reporter assay failed to identify causative nucleotide changes that led to the differential expression, monocyte chemotactic protein-1 (MCP-1) release from isolated monocytes were significantly higher in DS than in LEW. Intriguingly, this Ch10 QTL for blood pressure was also a possible QTL for urinary albumin excretion. Since Ccl2 is well known to be involved in various types of renal injury, it is likely that a higher expression of Ccl2 might aggravate macrophage infiltration, which in turn could aggravate tubulointerstitial injury, and thereby accelerate salt-sensitive hypertension. Thus, Ccl2 appears to be a interesting candidate gene for salt-sensitive hypertension in DS.
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PMID:The monocyte chemotactic protein-1 gene may contribute to hypertension in Dahl salt-sensitive rats. 1746 Mar 78

The arterial vessel wall response to a variety of injuries consists in structural changes, which can result in luminal narrowing and aggravation of the underlying disease. This arterial remodeling is characterized by neointima formation and medial thickening, inflammatory cell recruitment and endothelial dysfunction. Chemokines and the corresponding receptors have been shown to participate at every step of the remodeling process. The monocyte chemotactic protein (MCP)-1/CC motif receptor 2 (CCR2) axis induces monocyte infiltration of the injured vessel wall and can stimulate proliferation of smooth muscle cells (SMCs) in models of restenosis, cardiac allograft vasculopathy (CAV), pulmonary hypertension, and systemic hypertension. In contrast, stromal cell-derived factor (SDF)-1 alpha and its receptor CXC motif receptor 4 (CXCR4) are centrally involved in the neointimal recruitment of SMC progenitor cells (SPCs), presumably in response to SMC apoptosis, in restenosis and CAV. The RANTES (Regulated upon activation, normally T-cell expressed, and presumably secreted) receptors CC motif receptor 1 (CCR1) and CC motif receptor 5 (CCR5) affect intimal monocyte infiltration and neointimal growth, which could be due to the deposition of platelet-derived RANTES on activated endothelial cells. Fractalkine is expressed on neointimal SMCs and thus mediates the arrest of monocytes. Interestingly, reendothelialization of injured vessels appears to primarily depend on CXC motif ligand 1 (CXCL1). These chemokine effects form a complex network, which operates in all mechanisms of vascular remodeling. The detailed understanding of the function of the chemokine network in the remodeling process may allow specific disease intervention.
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PMID:Chemokines in vascular remodeling. 1747 83

Phosphodiesterase type 4 (PDE4) is involved in the hydrolysis of cAMP in pulmonary vascular smooth muscle (PA-SMC) and immune inflammatory cells. Given that intracellular cAMP accumulation inhibits contraction and growth of PA-SMCs as well as inflammatory cell functions, we investigated the effects of the PDE4 inhibitor 3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide (roflumilast), on pulmonary hypertension (PH) in rats. Treatment with roflumilast (0.5 or 1.5 mg x kg(-1) day(-1)) from day 1 to day 21 after monocrotaline (MCT) injection (60 mg x kg(-1) s.c.) attenuated PH development: pulmonary artery pressure, right ventricular hypertrophy, and muscularization of distal vessels on day 21 were decreased compared to control MCT-treated rats. Roflumilast (1.5 mg x kg(-1) day(-1)) also reduced the increases in interleukin-6 and monocyte chemotactic protein-1 mRNAs observed in lung tissue on day 21 without affecting the rise in interleukin-1beta mRNA on days 1 and 21. Roflumilast (1.5 mg x kg(-1) day(-1)) from day 21 to day 42 after MCT reversed established PH, almost normalizing pulmonary artery pressure and structure, and suppressing proliferating cell nuclear antigen-positive cells in pulmonary vascular walls. Treatment with roflumilast similarly attenuated PH development due to chronic hypoxia. Treatment of human PA-SMCs with roflumilast N-oxide, the active metabolite of roflumilast, at concentrations up to 10(-6) M, potentiated PA-SMC growth inhibition induced by prostacyclin (10(-6) M) or interleukin-1beta (10 ng x ml(-1)) but was inactive on its own. In conclusion, the PDE4 inhibitor roflumilast significantly attenuates pulmonary vascular remodeling and hypertension induced by chronic hypoxia or MCT and reverses established PH after MCT administration.
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PMID:Effects of roflumilast, a phosphodiesterase-4 inhibitor, on hypoxia- and monocrotaline-induced pulmonary hypertension in rats. 1938 93

Recent advances in basic and clinical research have identified Rho kinase as an important target potentially implicated in a variety of cardiovascular diseases. Rho kinase is a downstream mediator of RhoA that leads to stress fiber formation, membrane ruffling, smooth muscle contraction, and cell motility. Increased Rho-kinase activity is associated with vasoconstriction and elevated blood pressure. We identified a novel inhibitor of Rho kinase (SAR407899) and characterized its effects in biochemical, cellular, tissue-based, and in vivo assays. SAR407899 is an ATP-competitive Rho-kinase inhibitor, equipotent against human and rat-derived Rho-kinase 2 with inhibition constant values of 36 nM and 41 nM, respectively. It is highly selective in panel of 117 receptor and enzyme targets. SAR407899 is approximately 8-fold more active than fasudil. In vitro, SAR407899 demonstrated concentration-dependent inhibition of Rho-kinase-mediated phosphorylation of myosin phosphatase, thrombin-induced stress fiber formation, platelet-derived growth factor-induced proliferation, and monocyte chemotactic protein-1-stimulated chemotaxis. SAR407899 potently (mean IC(50) values: 122 to 280 nM) and species-independently relaxed precontracted isolated arteries of different species and different vascular beds. In vivo, over the dose range 3 to 30 mg/kg PO, SAR407899 lowered blood pressure in a variety of rodent models of arterial hypertension. The antihypertensive effect of SAR407899 was superior to that of fasudil and Y-27632. In conclusion, SAR407899 is a novel and potent selective Rho-kinase inhibitor with promising antihypertensive activity.
Hypertension 2009 Sep
PMID:Pharmacological characterization of SAR407899, a novel rho-kinase inhibitor. 1959 37

Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls. 409 COPD patients and 231 healthy subjects, aged 40-75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of >10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA. After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p<0.05), and higher levels of CRP (p<0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p<0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p<0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p<0.05). The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.
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PMID:Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study. 1964 42


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