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)

Elevations in plasma angiotensin II (AngII) are associated with evidence of vascular hyperpermeability expressed as efflux of plasma macromolecules into the perivascular and interstitial space. This exudative response is followed by a series of fibrogenic events that lead to a perivascular fibrosis of involved vessels. Mediators of hyperpermeability and fibrogenesis are unknown. In dogs receiving intravenous AngII, hemodynamic factors (i.e., arterial hypertension or coronary venoconstriction) were discounted as being responsible for the rise in cardiac lymph-to-plasma protein ratio. Accordingly, we investigated the relationship between AngII-induced coronary hyperpermeability and the release of prostaglandin E2 (PGE2) and activation of the basement membrane degrading matrix metalloproteinase, gelatinase/type IV collagenase. In dogs, cardiac lymph was monitored over the course of a 90-minute intravenous infusion of either AngII (0.2 to 0.3 micrograms/kg/min; n = 8) or saline solution (n = 6). Lymph was examined at 30-minute intervals for the following: total protein (Lowry's method), albumin (sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)), plasma fibronectin (SDS-PAGE and enzyme-linked immunosorbent assay); PGE2 (radioimmunoassay) and gelatinase/type IV collagenase (zymography). In comparison with baseline we found a consistent rise in lymph flow (p = 0.02), total protein (p = 0.02), albumin, fibronectin, PGE2 (p = 0.03), and gelatinase/type IV collagenase (p = 0.019), which began after 30 minutes of AngII infusion. Similar trends were not observed in dogs receiving saline solution alone. We therefore conclude that AngII-induced coronary vascular hyperpermeability is associated with an early release of PGE2 and gelatinase.
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PMID:Coronary vascular hyperpermeability and angiotensin II. 766 80

The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.
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PMID:Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice. 965 63

It was found in our previous paper that edema, proteinuria, hypertension (EPH)-gestosis-associated accumulation of collagen in the umbilical cord artery (UCA) is a result of increased biosynthesis and decreased degradation of this protein. It is known that the activity of collagenolytic enzymes is a main factor regulating collagen degradation rate in various tissues. For this reason it was decided to evaluate the effect of EPH-gestosis on the activity of proteolytic enzymes which may be involved in collagen degradation in the UCA wall. Proteolytic activity against bovine serum albumin, reconstituted collagen fibres and gelatin were evaluated. Latent forms of proteolytic enzymes were activated by the action of trypsin, p-chloromercuric benzoate (PCMB) and p-aminophenylmercuric acetate (APMA). A low activity of gelatinase (type IV collagenase) was detected in the extracts from the wall of the umbilical cord artery. This enzyme increased its activity several times after the action of trypsin, PCMB and APMA. EPH-gestosis results in a distinct reduction in gelatinase activity. Despite the action of activating agents the gelatinase from EPH-gestosis UCAs was considerably lower in comparison to control UCAs. It can be concluded that gelatinase of the umbilical cord artery forms an inactive complex with a tissue inhibitor of metalloproteinases. Such a complex dissociates under the action of trypsin, PCMB or APMA or sodium dodecyl sulphate. The decrease of gelatinolytic activity in the umbilical cord artery may be a factor that reduces the breakdown of collagen in the arterial wall and promotes an accumulation of this protein. The accumulation of collagen with simultaneous reduction in elastin content in the UCA may be the factors which reduce the elasticity of arterial wall and decrease the blood flow in the fetus of woman with EPH-gestosis.
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PMID:EPH-gestosis (pre-eclampsia)-induced decrease of gelatinase activity may promote an accumulation of collagen in the umbilical cord artery. 1069 Jun 79

Preeclampsia is a common pregnancy complication in the latter half of gestation diagnosed by hypertension and proteinuria. A key feature of preeclampsia is an altered placentation with reduced trophoblast invasion. Normal placentation requires controlled invasion of trophoblasts into the maternal uterine wall, with secretion of specific proteolytic enzymes able to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). 8-Iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo and is biologically active. We have recently reported an elevated content of free 8-iso-PGF(2alpha) in preeclamptic gestational tissue at delivery. Assuming an elevated level of 8-iso-PGF(2alpha) during the invasion period of the pregnancy, we hypothesized that 8-iso-PGF(2alpha) could reduce invasion of JAR cells, a choriocarcinoma cell line. We investigated JAR cell invasion with 2 types of Transwell assays and demonstrated that 8-iso-PGF(2alpha) (10 micromol/L) resulted in reduced cell invasion in both the colorimetric and radioactivity Transwell assays (P<0.01). Zymograms revealed reduced MMP-2 and MMP-9 activity in conditioned media from JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) (P<0.02). 8-Iso-PGF(2alpha) (10 micromol/L) also reduced the collagenase type IV activity in the conditioned media of JAR cells (P=0.04). No effects on MMP-2 and MMP-9 mRNA levels were observed after incubation with 8-iso-PGF(2alpha) (10 micromol/L), whereas protein levels were significantly decreased (P<0.02), suggesting a posttranscriptional regulation. We hypothesize a potential role for 8-iso-PGF(2alpha) in the reduced trophoblast invasion in preeclampsia.
Hypertension 2000 Jun
PMID:8-Iso-prostaglandin f(2alpha) reduces trophoblast invasion and matrix metalloproteinase activity. 1085 82

Oedema/proteinuria/hypertension (EPH) gestosis is one of the more common complications observed during pregnancy. Our previous studies demonstrated some qualitative and quantitative changes in the extracellular matrix of Wharton's jelly in newborns delivered by mothers with EPH gestosis. For this reason it was decided to evaluate the effect of EPH gestosis on the activity of gelatinolytic and proteolytic enzymes which may be involved in collagen degradation in Wharton's jelly. Zymographic analysis of control and EPH gestosis samples of Wharton's jelly demonstrates different electrophoretic patterns of gelatinolytic enzymes. The control Wharton's jelly contains two latent forms of gelatinolytic enzymes: gelatinase A [metalloproteinase (MMP)-2, 72 kD] and gelatinase B (MMP-9, 92 kD). In contrast to control tissue, the main gelatinolytic enzyme of EPH gestosis Wharton's jelly is gelatinase A (MMP-2). It was found that the proteolytic activity in EPH gestosis Wharton's jelly differs from control. The decrease in gelatinase activity may be one of the factors which promote the accumulation of collagen in this tissue.
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PMID:The activity of collagen-degrading enzymes of Wharton's jelly in EPH gestosis (pre-eclampsia). 1158 83

Glomerular hypertension has been established as a major factor contributing to glomerular scarring. Underlying cellular mechanisms leading to matrix accumulation are largely unknown. The isolated effect of oscillating hyperbaric pressure [OP; P(max) 50 mmHg (1 mmHg=0.133 kPa), P(mean) 24 mmHg, with a fixed oscillation of 60/min] on matrix-degrading protease secretion by rat mesangial cells (MCs) was analysed using a pressure chamber model described previously [Mertens, Espenkott, Venjakob, Heintz, Handt and Sieberth (1998) Hypertension 32, 945-952]. MCs were grown under atmospheric pressure (AP) or a controlled OP, and protease synthesis and gene transcription were analysed. A distinct biphasic cellular response to OP with stimulated gelatinase A protein expression and enzyme activity during the initial 24 h, and subsequent inhibition, was apparent, as shown by gelatin zymography. Gelatinase B activity remained unchanged. The abundance of gelatinase A transcripts, determined by reverse transcriptase-PCR, indicated a concordant regulation of gene transcription. To elucidate underlying regulatory events, reporter constructs were transfected. In these experiments, a recently identified response element, RE-1, conferred a significant stimulatory effect within the initial 4 h of OP. Nuclear protein/RE-1 binding studies revealed additional complexes from 5 min up to 3 h after OP exposure, with intensities dependent on P(max). STAT3 was identified as a component of these novel complexes. Down-regulation of cis-activity after 48 h of OP exposure was not transferred via the proximal 1686 bp of the gelatinase A regulatory sequence. In conclusion, hyperbaric OP elicits time-dependent changes in rat MC gelatinase A gene transcription.
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PMID:Mesangial cell gelatinase A synthesis is attenuated by oscillating hyperbaric pressure. 1187 97

This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed. Messenger RNA (mRNA) expression of renal preproendothelin-1, endothelin A and B receptors, and procollagen I and III was evaluated by reverse transcription polymerase chain reaction. Expression of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) was determined by immunoblotting. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography. In salt-loaded SHRSPs, preproendothelin-1 mRNA expression was increased 1.6-fold, and endothelin A receptor mRNA expression was decreased (70% of control). Salt-loaded SHRSPs had increased renal expression of TGF-b1 and procollagens. MMP-2 activity was augmented fivefold. BMS decreased (p < 0.01) expression of TGF-beta1, bFGF, and procollagen I and reduced MMP-2 activity. Thus severe hypertension and renal dysfunction in salt-loaded SHRSPs are associated with increased expression of renal endothelin-1, growth factors, and collagen. BMS treatment alleviated these effects, suggesting that nephroprotection by endothelin A receptor blockade is mediated by normalizing expression of growth factors, reducing extracellular matrix deposition, and decreasing MMP activity.
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PMID:Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats. 1202 84

Accumulation of interstitial collagen (fibrosis) between the endothelium and myocytes is one of the hallmarks of cardiac failure in renovascular hypertension (RVH). Renal insufficiency increases plasma homocysteine (Hcy), and levels of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are inversely related to plasma Hcy levels. We hypothesize that in RVH, accumulation of collagen between the endothelium and myocytes leads to endothelial-myocyte disconnection and uncoupling, in part, by hyperhomocysteinemia. Furthermore, we hypothesize that Hcy increases reactive oxygen species, generates nitrotyrosine, activates latent matrix metalloproteinase, and decreases the levels of endothelial nitric oxide in response to antagonizing PPAR-gamma. To create RVH in mice, the left renal artery was clipped with 0.4-mm silver wire for the 2 kidney, 1 clip (2K1C) method. Sham surgery was used as a control. To induce PPAR-gamma, 8 microg/mL ciglitazone (CZ) was administered to drinking water 2 days before surgery and continued for 4 weeks. Mice were grouped as 2K1C, sham, 2K1C+CZ, or sham+CZ (n = 6 in each group). Plasma Hcy increased 2-fold in the 2K1C-treated group (p < 0.05) as compared with the sham, and CZ had no effect on Hcy levels as compared to the 2K1C-treated group. Hcy binding in cardiac tissue homogenates decreased in the 2K1C-treated group but was substantially higher in the CZ-treated group. Cardiac reactive oxygen species levels were increased and endothelial nitric oxide were decreased in the 2K1C-treated group. Matrix metalloproteinase-2 and -9 activities were increased in the 2K1C-treated group compared with the control. Levels of cardiac inhibitor of metalloproteinase were decreased, whereas there was no change in tissue inhibitor of metalloproteinase-1 expression in the 2K1C-treated group vs. the sham-treated group. Collagen and nitrotyrosine levels were increased in the 2K1C-treated group, but mice treated with CZ showed lower levels comparatively. Cardiac transferase deoxyuridine nick-end labeling-positive cells were increased, and muscle cells were impaired in the 2K1C-treated mice vs. the sham-control mice. This was associated with decreased acetylcholine and bradykinin responses, which suggests endothelial-myocyte uncoupling in 2K1C-treated mice. Our results suggest that fibrosis between the endothelium and myocytes leads to an endothelial-myocyte disconnection and uncoupling by Hcy accumulation secondary to increased reactive oxygen species, nitrotyrosine, matrix metalloproteinase, and decreased endothelial nitric oxide in response to antagonizing PPAR-gamma.
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PMID:Homocysteine-dependent cardiac remodeling and endothelial-myocyte coupling in a 2 kidney, 1 clip Goldblatt hypertension mouse model. 1609 84

Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERalpha is not detectable in the adult lung. Lungs of adult female ERbeta knockout (ERbeta-/-) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ERbeta-/- mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ERbeta-/- mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta-/- mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1alpha and chemical adducts (with Hypoxyprobe), was evident in the heart, ventral prostate, periovarian sac, kidney, liver, and brain of ERbeta-/- mice under resting conditions. Furthermore, both male and female adult ERbeta-/- mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise. We conclude that ERbeta is necessary for the maintenance of the extracellular matrix composition in the lung and loss of ERbeta leads to abnormal lung structure and systemic hypoxia. Systemic hypoxia may be responsible for the reported left and right heart ventricular hypertrophy and systemic hypertension in ERbeta-/- mice.
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PMID:Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice. 1663 72

Atrial fibrillation (AF) may result from an electric conduction disturbance, increased hemodynamic stress, ischemia, inflammation, or remodeling in atria. Although genetic epidemiological studies have identified several genetic variants as risk factors for AF, the genetic determinants of this condition remain largely unknown. The purpose of the present study was to identify gene polymorphisms that confer susceptibility to lone AF. The study population comprised 1069 unrelated Japanese individuals, including 196 subjects with chronic lone AF and 873 controls. The genotypes for 40 polymorphisms of 32 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperchole-sterolemia as well as a stepwise forward selection procedure revealed that the -1306C-->T polymorphism of the matrix metalloproteinase 2 gene (MMP2) and the -592A-->C polymorphism of the interleukin 10 gene (IL10) were significantly (false discovery rate of <0.05) associated with the prevalence of AF. The T allele of the MMP2 polymorphism and the C allele of the IL10 polymorphism were a risk factor for and protective factor against AF, respectively. Determination of the genotypes for these polymorphisms may thus prove informative for assessment of the genetic component of AF.
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PMID:Genetic factors for lone atrial fibrillation. 1748 26


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