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)

Glomerular hypertension and hyperglycemia are major determinants of diabetic nephropathy. We sought to identify the mechanisms whereby stretch-induced activation of mesangial cell extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) is enhanced in high glucose (HG). Mesangial cells cultured on fibronectin Flex I plates in normal glucose (NG; 5.6 mM) or HG (30 mM), were stretched by 15% elongation at 60 cycles/min for up to 60 min. In HG, a 5-min stretch increased ERK1/ERK2 phosphorylation by 6.4 +/- 0.4/4.3 +/- 0.3-fold (P < 0.05 vs. NG stretch). In contrast, p38 phosphorylation was increased identically by stretch in NG and HG. Unlike many effects of HG, augmentation of ERK activity by HG was not dependent on protein kinase C (PKC) as indicated by downregulation of PKC with 24-h phorbol ester or inhibition with bisindolylmaleimide IV. In both NG and HG, pretreatment with arginine-glycine-aspartic acid peptide (0.5 mg/ml) to inhibit integrin binding or with cytochalasin D (100 ng/ml) to disassemble filamentous (F) actin, significantly reduced phosphorylation of ERK1/ERK2 and p38. To determine whether the rate of mitogen-activated protein kinase dephosphorylation is affected by HG, cellular kinase activity was inhibited by depleting ATP. Post-ATP depletion, phosphorylation of ERK1/ERK2 was reduced to 36 +/- 9/51 +/- 14% vs. 9 +/- 5/7 +/- 6% in NG (P < 0.05, n = 5). Thus stretch-induced ERK1/ERK2 and p38 activation in both NG and HG is beta(1)-integrin and F-actin dependent. Stretch-induced ERK1/ERK2 is enhanced in high glucose by diminished dephosphorylation, suggesting reduced phosphatase activity in the diabetic milieu. Enhanced mesangial cell ERK1/ERK2 signaling in response to the combined effects of mechanical stretch and HG may contribute to the pathogenesis of diabetic nephropathy.
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PMID:Stretch-induced mesangial cell ERK1/ERK2 activation is enhanced in high glucose by decreased dephosphorylation. 1099 19

In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH(2)-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT(1)) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT(1) receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT(1) receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT(1) receptor-mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
Hypertension 2000 Oct
PMID:Important role of angiotensin II-mediated c-Jun NH(2)-terminal kinase activation in cardiac hypertrophy in hypertensive rats. 1104 Feb 28

The activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was assessed in isolated rat mesenteric resistance arteries (200-micrometer diameter) in a pressure myograph and stimulated for 5 minutes by angiotensin II (Ang II, 0.1 micromol/L) with a pressure of 70 mm Hg. ERK1/2 activity was measured by using an in-gel assay, and ERK1/2 phosphorylation was measured by Western blot analysis with use of a phospho-specific ERK1/2 antibody. Ang II (0.1 micromol/L) induced contraction (28% of phenylephrine contraction, 10 micromol/L). ERK kinase inhibitor PD98059 (10 micromol/L) attenuated this contraction by 36% but not that to phenylephrine or K(+) (60 mmol/L). In unpressurized arteries, Ang II increased ERK1/2 activity by 26%, and pressure (70 mm Hg) itself increased ERK1/2 activity by 72%. Ang II and pressure together acted synergistically, increasing ERK1/2 activity by 264%. Thus, in pressurized vessels, Ang II (0.1 micromol/L) increased ERK1/2 activity by 112%, calculated as [(364/172)-1]x100, which was confirmed by a measured 72% increase in ERK1/2 phosphorylation. Ang II type 1 receptor blockade by candesartan (10 micromol/L) abolished the Ang II-induced increase in ERK1/2 activity, but Ang II type 2 receptor blockade (PD123319, 10 micromol/L) did not. The Ang II-induced increase in ERK1/2 activity was inhibited by protein kinase C inhibitors Ro-31-8220 (1 micromol/L) and Go-6976 (300 nmol/L) and tyrosine kinase inhibitors genistein (1 micromol/L, general) and herbimycin A (1 micromol/L, c-Src family). The present findings show for the first time in intact resistance arteries that ERK1/2 activation is rapidly regulated by Ang II, is synergistic with pressure, and is involved in contraction. The ERK1/2 signaling pathway apparently includes upstream protein kinase C and c-Src.
Hypertension 2000 Oct
PMID:Angiotensin II stimulates extracellular signal-regulated kinase activity in intact pressurized rat mesenteric resistance arteries. 1104 Feb 45

In our clinic 19615 patients were operated over 25 years on for goiter. Malignant thyroid neoplasms were found in 1049 (5.3%) patients including 875 (83.4%) women and 174 (16.6%) men. Sixty two adult patients (42 women and 20 men were operated on for medullary thyroid carcinoma (MTC). Thyroid cancer was diagnosed in this group pre or intraoperatively in 44 (71%) patients and postoperatively, on histologic examination, in 18 (29%) patients. These patients were reoperated. Radical operations (total thyroidectomy with regional lymph node removal) were conducted in 43 (69.3%) patients and palliative ones in 19 (30.7%) patients. After MTC surgery, MEN 2A (MTC and an adrenal tumor) were diagnosed by means of imaging techniques (USG, CT) in 6 (9.7%) patients. All adrenal tumors were unilateral. Five of these patients were operated, and pheochromocytoma was confirmed by histopathologic examination. Two years after the MTC operation, 1 women was lost to follow-up. After a year, she was admitted to hospital for severe hypertension and died of cerebral hemorrhagia. Pheochromocytoma was revealed by autopsy. All patients were treated complementarily after the MTC operation. Different combinations of teleradiotherapy, chemotherapy and substitutive doses of levothyroxine were used. Ten (23.2%) of 43 patients operated radically were reoperated 1-3 years after the first operation due to loco-regional tumor recurrence. Radical reoperations were performed in 4 patients, and palliative ones in 6. Over a 0.5-23-year follow-up period, 26 (41.9%) patients died, including 20 of cancer, and 6 of other reasons. Four out of 36 living patients have clinical or biochemical symptoms of neoplastic disease. The follow-up period of MEN 2 patients operated on ranged from 1 to 6 years. Up to now, no tumor in the second adrenal gland has been diagnosed in any of these patients. Genetic (molecular) tests performed in 31 out of 36 living patients revealed mutations of RET gene in 4 (12.9%).
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PMID:Medullary thyroid carcinoma (MTC)--clinical and molecular aspects on the basis of own experience. 1113 Feb 52

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 micromol/L, with a 3.6+/-0.6-fold induction in HPBM and a 4.8+/-0.9-fold induction in THP-1 cells at 1 micromol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 micromol/L) suppressed Ang II-induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R-mediated mechanism. Ang II-directed migration was also blocked by the Src kinase inhibitor PP2 (10 micromol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 micromol/L), and by the p38-MAPK inhibitor SB203580 (10 micromol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II-induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 micromol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7+/-0.9-fold induction and after 2 minutes for paxillin with a 3.2+/-0.4-fold induction. Ang II-induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R-dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.
Hypertension 2001 Feb
PMID:Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes. 1123 Mar 39

Systemic hypertension exacerbates diabetic retinopathy and other coexisting ocular disorders through mechanisms that remain largely unknown. Increased vascular permeability and intraocular neovascularization characterize these conditions and are complications primarily mediated by vascular endothelial growth factor (VEGF). Because systemic hypertension increases vascular stretch, we evaluated the expression of VEGF, VEGF-R2 (kinase insert domain-containing receptor [KDR]), and VEGF-R1 (fms-like tyrosine kinase [Flt]) in bovine retinal endothelial cells (BRECs) undergoing clinically relevant cyclic stretch and in spontaneously hypertensive rat (SHR) retina. A single exposure to 20% symmetric static stretch increased KDR mRNA expression 3.9 +/- 1.1-fold after 3 h (P = 0.002), with a gradual return to baseline within 9 h. In contrast, BRECs exposed to cardiac-profile cyclic stretch at 60 cpm continuously accumulated KDR mRNA in a transcriptionally mediated, time-dependent and stretch-magnitude-dependent manner. Exposure to 9% cyclic stretch increased KDR mRNA expression 8.7 +/- 2.9-fold (P = 0.011) after 9 h and KDR protein concentration 1.8 +/- 0.3-fold (P = 0.005) after 12 h. Stretched-induced VEGF responses were similar. Scatchard binding analysis demonstrated a 180 +/- 40% (P = 0.032) increase in high-affinity VEGF receptor number with no change in affinity. Cyclic stretch increased basal thymidine uptake 60 +/- 10% (P < 0.001) and VEGF-stimulated thymidine uptake by 2.6 +/- 0.2-fold (P = 0.005). VEGF-NAb reduced cyclic stretch-induced thymidine uptake by 65%. Stretched-induced KDR expression was not inhibited by AT1 receptor blockade using candesartan. Hypertension increased retinal KDR expression 67 +/- 42% (P < 0.05) in SHR rats compared with normotensive WKY control animals. When hypertension was reduced using captopril or candesartan, retinal KDR expression returned to baseline levels. VEGF reacted similarly, but Flt expression did not change. These data suggest a novel molecular mechanism that would account for the exacerbation of diabetic retinopathy by concomitant hypertension, and may partially explain the principal clinical manifestations of hypertensive retinopathy itself. Furthermore, these data imply that anti-VEGF therapies may prove therapeutically effective for hypertensive retinopathy and/or ameliorating the deleterious effects of coexistent hypertension on VEGF-associated disorders such as diabetic retinopathy.
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PMID:Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2: potential mechanisms for exacerbation of diabetic retinopathy by hypertension. 1127 59

Endothelin-converting enzyme 1 (ECE-1, EC 3.4.24.71) is a zinc-dependent type II mammalian membrane protein comprising the active site in the ectodomain. It exists in multiple splice variants that all catalyze the last and rate-limiting step in the activation of preproendothelin to the highly potent vasoconstrictor endothelin. There is high interest in finding small and potent inhibitors for this enzyme that could be used in numerous indications, e.g. hypertension. Since there is no structural information available for this important enzyme, we built a model of the complete ectodomain using the recently solved structure of human NEP as template. The naturally derived metalloproteinase inhibitor phosphoramidon was docked in the active site of this model and comparisons with the respective NEP complex were made.
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PMID:A three-dimensional model of endothelin-converting enzyme (ECE) based on the X-ray structure of neutral endopeptidase 24.11 (NEP). 1143 56

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

Stretch-induced expression of vascular endothelial growth factor (VEGF) is thought to be important in mediating the exacerbation of diabetic retinopathy by systemic hypertension. However, the mechanisms underlying stretch-induced VEGF expression are not fully understood. We present novel findings demonstrating that stretch-induced VEGF expression in retinal capillary pericytes is mediated by phosphatidylinositol (PI) 3-kinase and protein kinase C (PKC)-zeta but is not mediated by ERK1/2, classical/novel isoforms of PKC, Akt, or Ras despite their activation by stretch. Cardiac profile cyclic stretch at 60 cpm increased VEGF mRNA expression in a time- and magnitude-dependent manner without altering mRNA stability. Stretch increased ERK1/2 phosphorylation, PI 3-kinase activity, Akt phosphorylation, and PKC-zeta activity. Signaling pathways were explored using inhibitors of PKC, MEK1/2, and PI 3-kinase; adenovirus-mediated overexpression of ERK, PKC-alpha, PKC-delta, PKC-zeta, and Akt; and dominant negative (DN) mutants of ERK, PKC-zeta, Ras, PI 3-kinase and Akt. Although stretch activated ERK1/2 through a Ras- and PKC classical/novel isoform-dependent pathway, these pathways were not responsible for stretch-induced VEGF expression. Overexpression of DN ERK and Ras had no effect on VEGF expression in these cells. In contrast, DN PI 3-kinase as well as pharmacologic inhibitors of PI 3-kinase blocked stretch-induced VEGF expression. Although stretch-induced PI 3-kinase activation increased both Akt phosphorylation and activity of PKC-zeta, VEGF expression was dependent on PKC-zeta but not Akt. In addition, PKC-zeta did not mediate stretch-induced ERK1/2 activation. These results suggest that stretch-induced expression of VEGF involves a novel mechanism dependent upon PI 3-kinase-mediated activation of PKC-zeta that is independent of stretch-induced activation of ERK1/2, classical/novel PKC isoforms, Ras, or Akt. This mechanism may play a role in the well documented association of concomitant hypertension with clinical exacerbation of neovascularization and vascular permeability.
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PMID:Stretch-induced retinal vascular endothelial growth factor expression is mediated by phosphatidylinositol 3-kinase and protein kinase C (PKC)-zeta but not by stretch-induced ERK1/2, Akt, Ras, or classical/novel PKC pathways. 1169 3

Vasopeptidase inhibitors are a new class of drugs capable of inhibiting both angiotensin-converting enzyme and neutral endopeptidase 24.11. This involves simultaneous inhibition with a single molecule of two key enzymes, ACE and NEP, which are both involved in the regulation of cardiovascular homeostasis in many ways. This includes metabolism of several vasoactive peptides and their clearance from the circulation, therefore contributing to neurohumoral modulation, which might have therapeutic advantages in the prevention of endothelial dysfunction in hypertension.
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PMID:Vasopeptidase inhibition and endothelial function in hypertension. 1171


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