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)

Angiotensin II (AngII) mediates proinflammatory properties by activating NF-kappaB transcription factor nuclear translocation and inducing the expression of chemokines. For examination of whether AngII modulates the expression of Toll-like receptor 4 (TLR4), a key element of the innate immune system that senses LPS, mouse mesangial cells (MMC) were treated with AngII. AngII upregulated TLR4 mRNA and protein in MMC, and this effect was mediated through AngII type 1 receptors. Reporter gene experiments indicate that an activating protein-1 (AP-1) as well as an E-26 specific sequence (Ets) binding site in the TLR4 promoter are responsible for the AngII-stimulated transcriptional activity of the TLR4 gene. Preincubation of MMC with AngII enhanced LPS-induced NF-kappaB activation and chemokine expression. Immunohistochemical analyses revealed that double-transgenic rats that overexpressed human renin and angiotensinogen expressed higher levels of glomerular TLR4 compared with normal Sprague-Dawley rats. In vivo, infusion with AngII but not with norepinephrine into rats for 7 d also enhanced glomerular NF-kappaB activation after systemic application of LPS, suggesting that the effects are independent of concomitantly induced hypertension. Together, these observations suggest that AngII leads to an activation of the innate immune system by a novel mechanism involving the upregulation of TLR4. Our data contribute to a better understanding of how exogenous infections may trigger renal autoimmune processes, particularly in pathophysiologic situations with high renal AngII concentrations. Because TLR4 binds endogenous ligands (e.g., extracellular matrix components) in addition to microbial products, AngII-mediated upregulation of TLR4 also could be relevant for the development of inflammation in many noninfectious renal diseases.
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PMID:Angiotensin II upregulates toll-like receptor 4 on mesangial cells. 1667

Acute right ventricular (RV) failure following pulmonary embolism (PE) is a strong predictor of poor clinical outcome. Present studies test for an association between RV failure from experimental PE, inflammation, and upregulated chemokine expression. Additional experiments test if neutrophil influx contributes to RV dysfunction. PE was induced in male rats by infusing 24 microm microspheres (right jugular vein) producing mild hypertension (1.3 million beads/100 g, PE1.3), or moderately severe hypertension (2.0 million beads/100 g, PE2.0). Additional rats served as vehicle sham (0.01% Tween 20, Veh). In vivo RV peak systolic pressures (RVPSP) increased significantly, and then declined following PE2.0 (51 +/- 1 mm Hg 2 h; 49 +/- 1, 6 h; 44 +/- 1, 18 h). RV generated pressure of isolated, perfused hearts was significantly reduced in PE2.0 compared with PE1.3 or Veh. MCP-1 protein (ELISA) was elevated 21-fold and myeloperoxidase activity 95-fold in RV of PE2.0 compared with Veh or PE1.3. CINC-1, CINC-2, MIP-2, MCP-1, and MIP-1alpha mRNA also increased in RV of PE2.0. Histological analysis revealed massive accumulation of neutrophils (selective esterase stain) and monocyte/macrophages (CD68, ED-1) in RV of PE2.0 hearts in regions of myocyte damage. Electron microscopy showed myocyte necrosis and phagocytosis by inflammatory cells. LV function was normal and did not show increased inflammation after PE2.0. Treatment with anti-PMN antibody reduced RV MPO activity and prevented RV dysfunction. Conclusions-PE with moderately severe pulmonary hypertension (PE2.0) resulted in selective RV dysfunction, which was associated with increased chemokine expression, and infiltration of both neutrophils and monocyte/macrophages, indicating that a robust immune response occurred with RV damage following experimental PE. Experimental agranulocytosis reduced RV, suggesting that neutrophil influx contributed to RV damage.
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PMID:Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats. 1681 20

The authors have previously shown that arterial wall strain mediates the development of vessel wall inflammation in experimental hypertension. The current studies explore the mechanoregulation of monocyte chemoattractant protein-1 (MCP-1), a potent pro-inflammatory chemokine, by mitogen-activated protein kinases (MAPK) and oxidative stress. Rat aortic smooth muscle (RASM) cells were subjected to cyclic strain on a uniform biaxial strain device. Strain rapidly activated both ERK1/2(MAPK) and p38(MAPK), with peak activation at 5 min. Strain induced a twofold increase in MCP-1 mRNA, which was attenuated by PD 98059, a specific ERK1/2(MAPK) inhibitor, and SB 203580, a specific p38(MAPK) inhibitor. Cyclic strain also increased production of superoxide anion via an NADPH oxidase-dependent mechanism. To assess the potential role of reactive oxygen species in MAPK activation, cells were stretched in the presence of N-acetylcysteine, which had no effect on p38(MAPK) activation, but significantly inhibited ERK1/2(MAPK) activation and MCP-1 expression. In conclusion, redox-sensitive activation of ERK1/2(MAPK) and redox-insensitive activation of p38(MAPK) regulate straininduced MCP-1 expression in RASM cells. These findings define a role for MAPK signal transduction in establishing a pro-inflammatory state in the arterial wall, and thus implicate a potential molecular link between arterial wall strain and atherosclerosis.
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PMID:Mechanoregulation of monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. 1698 3

The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-gamma. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy.
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PMID:Antihypertensive therapy induces compartment-specific chemokine expression and a Th1 immune response in the clipped kidney of Goldblatt hypertensive rats. 1706 48

Dihydropyridine-based calcium antagonists are among the most widely used drugs for the treatment of hypertension. Since azelnidipine is a highly lipid-soluble dihydropyridine-based calcium antagonist with high vascular affinity, it is conceivable that azelnidipine could play a protective role against atherosclerosis. The aim of this study was to determine whether azelnidipine could suppress the expression of monocyte chemoattractant protein-1, a principal chemokine which mediates the recruitment of monocytes to the vasculature, in tumour necrosis factor (TNF)-alpha-exposed human umbilical vein endothelial cells. TNF-alpha, at a concentration of 10 ng/ml, upregulated monocyte chemoattractant protein-1 mRNA levels about seven-fold. Azelnidipine, 10 nmol/l, was found to inhibit the TNF-alpha-induced upregulation of monocyte chemoattractant protein-1 mRNA levels in human umbilical vein endothelial cells significantly. Furthermore, azelnidipine suppressed TNF-alpha-induced monocyte chemoattractant protein-1 production by human umbilical vein endothelial cells. This study demonstrates a novel beneficial aspect of azelnidipine, whereby azelnidipine could play a protective role against atherosclerosis by suppressing monocyte chemoattractant protein-1 overexpression in endothelial cells.
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PMID:Azelnidipine, a new long-acting calcium-channel blocker, inhibits tumour necrosis factor-alpha-induced monocyte chemoattractant protein-1 expression in endothelial cells. 1729

Hypertension is a known risk factor for the development of atherosclerosis. To assess how mechanical factors contribute to this process, mouse carotid arteries were maintained in organ culture at normal (80 mm Hg) or high (150 mm Hg) intraluminal pressure for 1, 6, 12, or 24 hours. Thereafter, fluorescent human monocytic cells (U937) were injected intraluminally and allowed to adhere for 30 minutes before washout. U937 adhesion was increased in vessels kept at 150 mm Hg 12 hours (23.5+/-5.7 versus 9.9+/-2.2 cells/mm at 80 mm Hg; P<0.05) or 24 hours (26.7+/-5.7 versus 8.8+/-1.5 cells/mm; P<0.05). At 24 hours, high pressure was associated with increased mRNA expression of monocyte chemoattractant protein-1, interleukin-6, keratinocyte-derived chemokine, and vascular cell adhesion molecule-1 (6.9+/-2.1, 4.4+/-0.1, 9.8+/-2.8, and 2.4+/-0.1-fold respectively; P<0.05), as assessed by quantitative RT-PCR and corroborated by immunohistochemistry, which also revealed an increase in intracellular adhesion molecule-1 expression. Nuclear factor kappaB inhibition using SN50 peptide abolished the overexpression of chemokines and adhesion molecules and reduced U937 adhesion in vessels at 150 mm Hg. Moreover, treatment of vessels and cells with specific neutralizing antibodies established that monocyte chemoattractant protein-1, interleukin-6, and keratinocyte-derived chemokine released from vessels at 150 mm Hg primed the monocytes, increasing their adhesion to vascular cell adhesion molecule-1 but not intracellular adhesion molecule-1 via alpha4beta1 integrins. The additive effect of chemokines on the adhesion of U937 cells to vascular cell adhesion molecule-1 was confirmed by in vitro assay. Finally, pressure-dependent U937 adhesion was blunted in arteries from mice overexpressing endothelial NO synthase. Hence, high intraluminal pressure induces cytokine and adhesion molecule expression via nuclear factor kappaB, leading to monocytic cell adhesion. These results indicate that hypertension may directly contribute to the development of atherosclerosis through nuclear factor kappaB induction.
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PMID:High pressure promotes monocyte adhesion to the vascular wall. 1739 76

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

Circulating monocytes from hypertensive patients show elevated secretion patterns of pro-inflammatory cytokines, an increased expression of adhesion molecules, and an increased adhesion to vascular endothelial cells. We tested the hypothesis that telmisartan, an angiotensin II type 1 (AT(1)) receptor antagonist, reduces the activation of circulating monocytes from hypertensive patients and diminishes the monocyte-endothelial cell adhesion. Monocytes of 20 hypertensive patients and 20 normotensive controls were isolated by density gradient centrifugation and Dynabeads, and the monocyte adhesion to human aortic endothelial cell monolayers was measured by adhesion assays. To characterize monocyte activation we assessed the expression of activity-related cell surface markers that are also involved in monocyte adhesion to endothelial cells, such as CD11a/b and CD54, as well as the chemokine receptors CCR1, CCR2 and CCR5 before and after telmisartan therapy using flow cytometry. Spontaneous adhesion of monocytes from hypertensive patients and the adhesion after stimulation with angiotensin II were significantly increased compared with those in normotensive controls (p<0.05). Treatment of hypertensive patients with the AT(1) receptor antagonist telmisartan significantly diminished the adhesion of circulating monocytes to human endothelial cells (p=0.02) despite the increase in the expressions of CD11b, CD54 and CCR5 after telmisartan therapy. Reducing monocyte adhesion may be a novel beneficial effect of the AT(1) receptor antagonist telmisartan helping to prevent vascular alterations in hypertension. The mechanism of action remains to be elucidated, since reduction in monocyte adhesion was not attributable to changes in adhesion molecule expression.
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PMID:Effects of the angiotensin II type 1 receptor antagonist telmisartan on monocyte adhesion and activation in patients with essential hypertension. 1766 55

Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-gamma-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARgamma in this context. CD4-positive lymphocytes express both the AT1R and PPARgamma. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1+/-3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6+/-0.7-fold induction at 10 mumol/L of telmisartan (P<0.01 compared with SDF-1-treated cells; n=22). Three different PPARgamma activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPARgamma-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPARgamma small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARgamma. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPARgamma-activating properties.
Hypertension 2008 Feb
PMID:Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. 1815 51

High blood pressure (BP) and monocyte activation are associated with atherogenic processes. Especially, CD16 expressing monocytes are shown to be activated in many inflammatory conditions but their characteristics in hypertension is unknown. We compared CD16(++), CD16(+) and CD16(-) monocyte populations and their cellular adhesion molecule (CAM), chemokine receptor, and activation marker expression in response to a moderate 20-min treadmill exercise bout at 65-70% V O(2peak) in 44 participants with elevated (EBP) or normal BP (NBP). Blood was drawn before, immediately after, and 10min after exercise. Phenotyping of monocytes and detection of surface markers were done by flow cytometry. Monocyte subset by exercise [pre, post, 10-min post] repeated measures ANOVA and group [EBP vs. NBP] by exercise repeated measures of ANCOVA with age, BMI, and fitness as covariates were employed. Circulating numbers of all the three monocyte subsets increased after exercise (p<0.001), with the largest % increase for CD16(+)CD14(++). Percents of CD16(++)CD14(+) and CD16(+)CD14(++) increased, whereas % CD16(-)CD14(++) decreased (p<0.001). Also, pre to post exercise changes in CD62L, CD11b, CXCR2, and HLA-DR expression were different among the monocyte subsets (p's<0.001). BP status did not significantly affect monocyte subset trafficking, although post-exercise changes in CD62L and CXCR2 levels were greater in EBP individuals (p<0.05). We conclude that exercise leads to a different mobilization among monocyte subsets based on CD16 expression. Individuals with high BP showed greater responses to a physical challenge in some monocyte chemokine receptors and selectins, but its clinical implications need further examination.
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PMID:Effects of an exercise challenge on mobilization and surface marker expression of monocyte subsets in individuals with normal vs. elevated blood pressure. 1824 48


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