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)

The leukocyte- type 12/15-Lipoxygenase (12/15-LO) enzyme and its oxidized lipid products play important roles in vascular smooth muscle cell (VSMC) growth, migration, and matrix responses associated with hypertension, atherosclerosis, and restenosis. However, much less is known about their inflammatory effects. In this study, we showed that the 12/15-LO product of linoleic acid, 13-hydroperoxyocta decadienoic acid (13-HPODE) can transcriptionally upregulate the expression of the chemokine monocyte chemoattractant protein-1 (MCP-1) in VSMC. We also observed reduced activation of the transcription factor, NF-kappa B and reduced expression of MCP-1/JE mRNA in VSMC from 12/15-LO knock-out mice relative to WT. To confirm the role of NF-kappa B in 13-HPODE-induced MCP-1 expression and to selectively block the induction of such inflammatory genes in VSMC, we designed novel molecular approaches to knockdown NF-kappa B with short interfering RNAs (siRNAs). We designed siRNAs to human NF-kappa B p65 transcriptionally active subunit by using a rapid PCR-based approach that generates sense and antisense siRNA separated by a hairpin loop downstream of the U6 promoter. siRNA PCR products targeting seven different sites on p65 cDNA could induce upto 92% reduction in HA-p65 protein levels. A six-fold decrease in NF-kappa B-dependent luciferase activity was also seen. Transfection of human VSMC with these siRNA PCR products resulted in 70% reduction in p65 protein levels. We cloned the PCR products into a pCR3.1 vector and these p65 siRNA expressing plasmids very effectively blocked 13-HPODE-induced expression of both MCP-1 and TNF-alpha genes. These results show for the first time that 13-HPODE can induce MCP-1 in the vasculature via activation of NF-kappa B.
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PMID:Regulation of monocyte chemoattractant protein-1 by the oxidized lipid, 13-hydroperoxyoctadecadienoic acid, in vascular smooth muscle cells via nuclear factor-kappa B (NF-kappa B). 1508 18

We examined if there is systemic vascular inflammation and neutrophil infiltration in women with preeclampsia. Resistance-sized vessels (10 to 200 microm) of subcutaneous fat were evaluated from normal nonpregnant women, normal pregnant women, and preeclamptic women. Immunohistochemical staining was performed for: (1) interleukin-8 (IL-8), a potent neutrophil chemokine; (2) intercellular adhesion molecule-1 (ICAM-1; CD54), an endothelial cell adhesion molecule; and (3) CD66b, a neutrophil antigen. Vessels of preeclamptic patients had intense IL-8 staining in the endothelium and vascular smooth muscle, as compared with little or no staining for normal pregnant and normal nonpregnant patients. ICAM-1 was expressed on the endothelium of all patient groups. In preeclamptic patients, ICAM-1 was also expressed on vascular smooth muscle. Vessels of preeclamptic patients had significantly more CD66b staining of neutrophils than did normal pregnant or normal nonpregnant patients. There were significantly more vessels stained, more vessels with neutrophils flattened and adhered to endothelium, more vessels with neutrophils infiltrated into the intima, and more neutrophils per vessel. In conclusion, in women with preeclampsia, there was significant infiltration of neutrophils into maternal systemic vasculature associated with inflammation of the vascular smooth muscle indicated by increased expression of IL-8 and ICAM-1. Neutrophil infiltration provides a reasonable explanation for endothelial and vascular smooth muscle dysfunction in preeclampsia because neutrophils produce toxic substances, which may explain clinical symptoms.
Hypertension 2004 Jul
PMID:Neutrophils infiltrate resistance-sized vessels of subcutaneous fat in women with preeclampsia. 1514 93

Recent studies suggest that the chemokine eotaxin may participate in atherosclerosis. Threonine (T) for alanine (A) substitution at amino acid 23 in the eotaxin gene (CCL11) has been associated with risk of developing allergic-inflammatory disorders. However, no genetic-epidemiological data are available on the risk of cardiovascular disease associated with this polymorphism. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we evaluated the A23T polymorphism among 523 individuals who subsequently developed myocardial infarction (MI) and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. The T23 allele was significantly associated with risk of myocardial infarction (odds ratio (OR) in an age and smoking adjusted recessive model of inheritance, 1.86; 95% confidence interval (CI), 1.15-3.01; P = 0.012). This risk effect remained statistically significant in analyses further controlling for body mass index, history of hypertension, the presence of diabetes, and randomized treatment assignment (OR, 1.95; 95% CI, 1.19-3.18; P = 0.008). In this cohort, a T for A substitution at amino acid 23 in the eotaxin gene is associated with increased risk for incident myocardial infarction. If confirmed in other cohorts, these data support the emerging hypothesis that eotaxin participates in atherosclerosis.
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PMID:Threonine for alanine substitution in the eotaxin (CCL11) gene and the risk of incident myocardial infarction. 1518 51

The leukocyte-type 12/15-lipoxygenase (12/15-LO) has been implicated in the pathogenesis of atherosclerosis, hypertension, and diabetes. 12/15-LO and its products are associated with LDL oxidation, cellular growth, migration, adhesion, and inflammatory gene expression in monocytes/macrophages, endothelial cells, and vascular smooth muscle cells (VSMCs). Our objective, therefore, was to develop novel expression vectors for short interfering RNAs (siRNAs) targeting 12/15-LO to evaluate its functional relevance in macrophages and VSMCs. We used a PCR-based approach to rapidly identify effective siRNA target sites on mouse 12/15-LO and initially tested their efficacy on a fusion construct of 12/15-LO cDNA and enhanced green fluorescent protein. We then cloned these U6 promoter+siRNA PCR products into plasmid vectors [short hairpin siRNAs (shRNAs)] to knockdown endogenous 12/15-LO expression in mouse macrophages and also rat and mouse VSMCs. Furthermore, the functional effects of shRNA-mediated 12/15-LO knockdown were noted by the reduced oxidant stress and chemokine [monocyte chemoattractant protein-1 (MCP-1)] expression in a differentiated mouse monocytic cell line as well as by the reduced cellular adhesion and fibronectin expression in VMSCs. Knocking down 12/15-LO expression also reduced the expression of inflammatory genes, MCP-1, vascular cell adhesion molecule-1, and interleukin-6 in VSMCs. Our results illustrate the functional relevance of 12/15-LO activation in macrophages and VSMCs and its relationship to oxidant stress and inflammation.
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PMID:Effects of silencing leukocyte-type 12/15-lipoxygenase using short interfering RNAs. 1557 42

Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis.
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PMID:Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. 1566 Mar 33

Hemodynamic abnormalities are important in the pathogenesis of the glomerular damage in diabetes. Glomerular macrophage infiltration driven by the chemokine monocyte chemoattractant protein-1 (MCP-1) is an early event in diabetic nephropathy. The thiazolidinedione rosiglitazone ameliorates albumin excretion rate in diabetic patients with microalbuminuria and has anti-inflammatory properties, raising the possibility of a relationship between its renoprotective and anti-inflammatory activity. Investigated was whether mesangial cell stretching, mimicking in vitro glomerular capillary hypertension, enhances MCP-1 expression and monocyte chemoattractant activity. The effect of the combination of stretch with high glucose on MCP-1 production was studied and, finally, the effect of rosiglitazone on these processes was assessed. Stretching of human mesangial cells significantly enhanced their monocyte chemoattractant activity. This effect was mediated by MCP-1 as it was paralleled by a significant rise in both MCP-1 mRNA and protein levels and was completely abolished by MCP-1 blockade. Combined exposure to both stretch and high glucose further increased MCP-1 production. Stretch activated the IkappaB-NF-kappaB pathway, and NF-kappaB inhibition, with the use of the specific inhibitor SN50, completely abolished stretch-induced MCP-1, indicating that stretch-induced MCP-1 was NF-kappaB dependent. The addition of rosiglitazone significantly diminished stretch-induced NF-kappaB activation, MCP-1 production, and monocyte chemotaxis. In conclusion, stretching of mesangial cells stimulates their monocyte chemoattractant activity via an NF-kappaB-mediated, MCP-1-dependent pathway, and this effect is prevented by rosiglitazone.
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PMID:Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone. 1567 12

Chemokine-driven migration of inflammatory cells has been implicated in pathogenesis of atherosclerosis-associated conditions such as ischemic stroke and myocardial infarction. In this study, a candidate chemokine, monocyte chemoattractant protein (MCP)-1, was investigated in patients with both aforementioned manifestations of atheroslerotic inflammation. MCP-1 levels in serum were determined by ELISA in 40 healthy, control subjects (C), 40 patients with ischemic stroke (IS), and in 64 patients with myocardial infarction (MI). Statistical analysis utilised Mann-Whitney test, Fisher's exact test, and Spearman's rank correlation (P < .05). In comparison to control subjects (C; median/interquartile range: 239/126 pg/mL), MCP-1 serum levels were increased in both investigated patient cohorts (IS: 384/370, P < .001; MI: 360/200, P < .002). There was a substantial variability of MCP-1 serum levels, especially in the IS group. No relationship was observed between chemokine levels and atherosclerosis risk factors (hypertension, diabetes, smoking, and alcohol consumption), and MCP-1 was also not related to age or gender. Elevation of MCP-1 in circulation of patients with atherosclerosis-associated complications implicates this CC chemokine ligand (CCL)2 in inflammatory processes, which contribute to pathogenesis of myocardial infarction and ischemic stroke. Further investigations, including patient stratification, are however necessary to evaluate if MCP-1 can be utilised for clinical management of patients with these diseases.
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PMID:Serum levels of the MCP-1 chemokine in patients with ischemic stroke and myocardial infarction. 1610 5

Hypertension, poor glycemic control and albuminuria are well known risk factors for diabetic nephropathy, but these factors do not explain all of the inter-individual variabilities in the rate of progression to kidney failure. Recent evidence showed that genetic predisposition affected the hyperglycemia-induced nephrotoxicity in patients with type 2 diabetes mellitus (DM). We reviewed the present state of knowledge concerning the relationship between genetics and diabetic nephropathy in type 2 DM. However, the results are inconclusive and the genetic determinants of diabetic nephropathy are not fully understood. In addition, genetic background of nephropathy in type 2 DM was thought to be more complex than in type 1 DM. Recent studies suggested that the inflammation would be an essential component of type 2 DM and its complications. We postulated that increased systemic and/or intrarenal inflammation in high glucose milieu is important in the pathogenesis of nephropathy in patients with type 2 DM. To investigate the impact of inflammation on diabetic nephropathy, we studied several polymorphisms in genes encoding inflammatory cytokine and chemokine in patients with type 2 DM. Among them, -511 C/T in interleukin-1beta (IL-1beta), tandem repeat in IL-1 receptor antagonist (IL-1Ra), -308 G/A in tumour necrosis factor-alpha (TNF-alpha) were significantly associated with an increased risk of kidney failure. In addition, some of them were remarkably different from those previously reported in the NCBI or literature based on the western population. Our results suggest that inflammation could play a pathogenic role in diabetic nephropathy in type 2 DM. A better understanding of genetic factors predisposing to diabetic nephropathy would not only help to identify diabetic patients at risk, but also be helpful to unveil the pathogenesis of DN.
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PMID:Genetics of diabetic nephropathy in type 2 DM: candidate gene analysis for the pathogenic role of inflammation. 1617 85

Understanding of the mechanisms underlying atherosclerotic disorders has evolved beyond the view of a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated inflammatory pathways as an important pathogenic mechanism in atherogenesis and plaque destabilization. Although not necessarily the primary event, inflammation and cytokine activation during plaque formation and destabilization may represent a common final pathway to various stimuli. Thus, it seems that not only 'new' risk factors, such as infections with various microorganisms, but also classic risk factors for cardiovascular disease, such as hyperlipidemia, hypertension and diabetes, may promote their atherogenic effects through inflammatory responses. Indeed, recent reports have suggested that traditional cardiovascular medications may attenuate atherogenesis and enhance plaque stability, at least partly through anti-inflammatory mechanisms. However, uncovering the inflammatory pathways in atherosclerosis has raised the possibility that newer treatment modalities should be more directly targeted against inflammatory mediators. Recently, a series of experimental studies have reported reduction of atherosclerosis by immunomodulatory therapy, such as chemokine blockade, interleukin-10 and immunization/vaccination against oxidized low-density lipoprotein and heat-shock protein. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies in coronary artery disease in humans.
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PMID:Inflammation in coronary artery disease: potential role for immunomodulatory therapy. 1629 1

Chemokines are crucial immune mediators in many physiological and pathophysiological conditions. Chemokines have been hypothesized to be involved in macrophage infiltration into adipose tissue in obesity and might therefore play an important role in the development of obesity-related disorders like type 2 diabetes. Out of 1,653 individuals aged 55-74 years participating in a population-based survey in southern Germany (the Kooperative Gesundheitsforschung in der Region Augsburg [KORA] [Cooperative Health Research in the Region of Augsburg] Survey S4, 1999-2001), 236 individuals with type 2 diabetes, 242 subjects with impaired glucose tolerance (IGT), and 244 normoglycemic control subjects were studied for circulating concentrations of interleukin (IL)-8; RANTES (regulated on activation, normal T-cell expressed, and secreted); interferon-gamma-inducible protein-10 (IP-10), and eotaxin. Systemic concentrations of RANTES were higher in individuals with IGT or type 2 diabetes than in control subjects, whereas IL-8 levels were elevated in type 2 diabetic patients only (P < 0.001 for all comparisons). IP-10 and eotaxin were not significantly associated with IGT or type 2 diabetes. Adjustment for age, sex, BMI, hypertension, LDL cholesterol, HDL cholesterol, uric acid, C-reactive protein, and IL-6 did not alter these findings. Our findings indicate that RANTES and IL-8 may be involved in the development of type 2 diabetes independent of metabolic syndrome-related risk factors and of each other. There is no general upregulation of chemokine production in type 2 diabetes, but rather an association of the disease with specific members of the chemokine family.
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PMID:Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). 1630 28


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