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)

Deoxycorticosterone acetate (DOCA)-salt-treated rats developed marked hypertension after 4 weeks with an increase in aortic endothelin-1. Treatment of DOCA-salt hypertensive rats with a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, significantly reduced the elevation in systolic blood pressure and the effect was accompanied by a decrease in aortic endothelin- content. Thus, a proteasome-dependent proteolytic pathway appears to play an important role in the enhanced production of endothelin-1 in blood vessels and the consequent increase in blood pressure in this model of hypertension.
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PMID:A proteasome inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats. 968 28

To search for a possible role for vascular proteasome in hypertension, we examined changes in proteasome level in aorta of deoxycorticosterone acetate (DOCA)-salt hypertensive rats and evaluated the antihypertensive effect of a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal (PSI). Two weeks after the start of DOCA-salt treatment, the rats, with systolic blood pressure being 154 +/- 5 mmHg, were randomly divided into two groups and were given PSI or its vehicle for 2 weeks. Vehicle-treated DOCA-salt rats developed marked hypertension after 4 weeks (198 +/- 9 mmHg), with increases in aortic proteasome activity and content. The systolic blood pressure was positively correlated with both the content and activity of aortic proteasome. The administration of PSI to DOCA-salt hypertensive rats suppressed the elevation of systolic blood pressure (144 +/- 4 mmHg), accompanied by decreases in aortic proteasome activity and content. These results suggest that proteasome production in vascular tissues is increased in DOCA-salt hypertensive rats, and that PSI exhibits antihypertensive effect in this experimental hypertensive model. Thus, the findings indicate the pathophysiological importance of increased vascular proteasome in the development of DOCA-salt hypertension.
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PMID:Antihypertensive effect of a proteasome inhibitor in DOCA-salt hypertensive rats. 969 41

1. In the present study, we investigated the potential of the proteasome inhibitor N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal (PSI) to prevent vascular hypertrophy induced by deoxycorticosterone acetate (DOCA) and salt in rats. 2. Vehicle (35% ethanol, 35% polyethylene glycol and 30% saline solution)-treated DOCA-salt rats developed marked hypertension at 4 weeks. Morphological studies on the rats given vehicle showed aortic hypertrophy, with a significant increase in wall thickness, wall area and wall-to-lumen ratio. A significant decrease in vascular wall hypertrophy was observed in PSI (3 mg/kg)-treated DOCA-salt rats. In addition, a marked increase in aortic endothelin (ET)-1 content was evident in vehicle-treated DOCA-salt rats compared with findings in sham-operated rats. A significant attenuation of this increase occurred in PSI-treated DOCA-salt rats. 3. These results indicate that PSI can prevent the vascular hypertrophy in DOCA-salt hypertensive rats and the effect is accompanied by suppression of ET-1 production in the aorta. We suggest that a proteasome-dependent proteolytic system has an important role in the development of vascular hypertrophy in cases of DOCA-salt-induced hypertension, possibly through the enhancement of ET-1 production in vascular tissues.
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PMID:A proteasome inhibitor prevents vascular hypertrophy in deoxycorticosterone acetate-salt hypertensive rats. 1138 May 24

The pathogenesis of salt-sensitive hypertension remains poorly defined, but a role for nitric oxide (NO) has been suggested. The Dahl/Rapp salt-sensitive rat possesses a defect in NO synthesis that is overcome by supplementation with L-arginine, which increases NO and cGMP production and prevents salt-sensitive hypertension. An S714P mutation of inducible NO synthase (NOS2) was subsequently identified. The current report examined the functional significance of an S714P mutation in NOS2. COS-7 cells were transiently transfected with cDNA of wild-type NOS2 and S714P and S714A mutants of NOS2, and enzyme function was determined. Whereas steady-state mRNA levels did not differ, immunoblot analysis demonstrated decreased levels of NOS2 protein. Metabolic labeling experiments confirmed a reduced half-life of the S714P mutation. Nitrite production, which was dependent on the concentration of L-arginine in the medium, was diminished in cells transfected with the S714P mutant, compared with the wild type and the S714A mutant. These data provide a biochemical explanation of the physiological abnormalities of NOS2 in the Dahl/Rapp salt-sensitive rat and suggest that a posttranslational mechanism involving the proteasome may be responsible for the diminished NO production observed in response to increased dietary salt intake in these animals.
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PMID:Nitric oxide synthase (NOS2) mutation in Dahl/Rapp rats decreases enzyme stability. 1150 43

Biochemical and pharmacological studies have suggested that NOS2 (inducible nitric oxide synthase) has a functional role in the blood pressure response to increases in dietary salt intake. On a high-salt diet, the Dahl/Rapp salt-sensitive (S) strain of rat, a genetic model of salt-sensitive hypertension, did not show increased nitric oxide production. NOS2 from S rats possesses a point mutation that results in substitution of proline for serine at position 714. In the present study, rat NOS2 was shown to be ubiquitinated in vitro and in vivo and to be degraded by the proteasome; this process was accelerated for the S714P mutant. Accelerated degradation of the S714P mutant enzyme accounted for the diminished enzyme activity of this mutant. Hsp90 (heat-shock protein 90) associated with NOS2 and modulated degradation, but was not responsible for the accentuated degradation of the S714P mutant enzyme. The combined findings demonstrate the integral role of ubiquitination and degradation by the proteasome in the regulation of NO production by rat NOS2. Demonstrating that this process is responsible for the abnormal function of the S714P mutant NOS2 in S rats confirms the physiological importance of the proteasome in NOS2 function.
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PMID:Accelerated ubiquitination and proteasome degradation of a genetic variant of inducible nitric oxide synthase. 1295 38

G protein-coupled receptor kinases (GRKs) are key modulators of G protein-coupled receptor signalling. Increasing evidence points to the occurrence of complex mechanisms able to modulate the subcellular localization, activity and expression levels of GRKs, revealing new functional interactions of these kinases with different cellular proteins and transduction cascades. GRK activity and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins, caveolin and calcium-sensing proteins. In addition, GRK phosphorylation by several other kinases has recently been shown to modulate its functionality, thus putting forward new feedback mechanisms connecting different signalling pathways to G protein-coupled receptors (GPCR) regulation. On the other hand, the mechanisms governing GRK expression at both transcriptional and protein stability levels are just beginning to be unveiled. Namely, GRK2 has been shown to be rapidly degraded by the proteasome pathway in a process dependent on beta-arrestin and c-Src function, and also to be proteolyzed by m-calpain. A better knowledge of GRK regulatory mechanisms would contribute to greater understanding of GRK physiological function and also its reported alterations in different pathological situations, such as congestive heart failure, hypertension or inflammation.
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PMID:Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. 1449 40

It has been known since the 1940s that a gradient of renal oxygenation exists in the kidney with the lowest PO2 in the renal inner medulla under physiological conditions. Due to a low PO2 milieu in the renal medulla, the cells in this region are at constant risk of hypoxic injury. Although numerous studies have shown that renal medullary cells adapt well to low PO2, the precise mechanism mediating this adaptive response remains poorly understood. Recently, hypoxia-induced molecular adaptation in mammalian tissues or cells has been studied extensively and many studies have indicated that the molecular regulation of gene expression is importantly involved. This paper focuses on the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1)-mediated molecular adaptation and explores the physiological relevance of molecular activation of HIF-1 and its target genes in the renal medulla. Given that this HIF-1-mediated action is associated with local redox status, evidence is presented to indicate that reactive oxygen species (ROS), especially superoxide (O) is importantly involved in HIF-1-mediated molecular adaptation in renal medullary cells. O degrades HIF-1alpha, an HIF-1 subunit, by activating ubiquitin-proteasome and thereby decreases the transcriptional activation of many oxygen-sensitive genes. This action of O disturbs renal medullary adaptation to low PO2 and produces renal medullary dysfunction, resulting in sodium retention and hypertension. This report also provides evidence indicating the primary source of O, enzymatic pathways for O production and activating mechanism of O production in the kidney. It is concluded that HIF-1-mediated molecular adaptation to low PO2 is of importance in the regulation of renal medullary function and that ROS may target this HIF-1-mediated medullary adaptation to damage renal function.
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PMID:Reactive oxygen species and molecular regulation of renal oxygenation. 1461 39

Neurokinin B (NKB) has recently been demonstrated to be secreted from the placenta in abnormally high amounts in preeclampsia (PE) and to cause hypertension in rats, suggesting it may be a mediator of some pathophysiological features of PE. It is also known that NKB receptors exist in the placenta. To determine the effect of high levels of NKB on the placenta, we have performed proteomics on five separate preparations of cultured purified human term cytotrophoblast cells. The results showed a statistically significant decrease in 20 proteins, of which five were unknown proteins. Proteins important in antioxidant defenses that decreased were thioredoxin, cyclophilin A, cytokeratin 1, and peroxiredoxin 5. Two proteins that inhibit intravascular anticoagulation, cytokeratin 1 and annexin 11 were also decreased. Pathways involving pro-inflammatory cytokine activation of NF-kappa B are opposed by Raf kinase inhibitor protein, which was also decreased. Cofilin 1, a protein involved in defense against bacteria, was also decreased. Among other proteins that were suppressed by NKB were proteasome proteins, desmoplakin, and calgizzarin. Western blots confirmed the decrease in cytokeratin 1 and cyclophilin A protein after NKB exposure. In PE, there is reduced antioxidant activity and increased intravascular coagulation. The findings that high levels of NKB, similar to those observed in PE, can impair these two classes of activity support the hypothesis that high NKB levels may contribute to the pathogenesis of PE.
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PMID:Functional proteomics of neurokinin B in the placenta indicates a novel role in regulating cytotrophoblast antioxidant defences. 1462 67

Focal segmental glomerulosclerosis (FSGS) is a common pattern of renal injury, seen as both a primary disorder and as a consequence of underlying insults such as diabetes, HIV infection, and hypertension. Point mutations in the alpha-actinin-4 gene ACTN4 cause an autosomal dominant form of human FSGS. We characterized the biological effect of these mutations by biochemical assays, cell-based studies, and the development of a new mouse model. We found that a fraction of the mutant protein forms large aggregates with a high sedimentation coefficient. Localization of mutant alpha-actinin-4 in transfected and injected cells, as well as in situ glomeruli, showed aggregates of the mutant protein. Video microscopy showed the mutant alpha-actinin-4 to be markedly less dynamic than the wild-type protein. We developed a "knockin" mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation. We used cells from these mice to show increased degradation of mutant alpha-actinin-4, mediated, at least in part, by the ubiquitin-proteasome pathway. We correlate these findings with studies of alpha-actinin-4 expression in human samples. "Knockin" mice with a disease-associated Actn4 mutation develop a phenotype similar to that observed in humans. Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 "knockin" and "knockout" mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms.
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PMID:Alpha-actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein. 1520 19

A proteasome-dependent proteolytic pathway serves important functions in cell cycle control and transcriptional regulation; however, its pathophysiological role in cardiovascular diseases is still unclear. We have recently obtained evidence that proteasome inhibitors are capable of preventing the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension or hypertrophy and of ischemic acute renal failure (ARF). Beneficial effects of the proteasome inhibitors were accompanied by a decrease in endothelin-1 (ET-1) content in the aorta and kidney of DOCA-salt and ischemic ARF animals, respectively. In addition, there is evidence showing that the reduction of nuclear factor-kappaB (NF-kappaB) activation is involved in the mechanisms for suppressive effects of proteasome inhibitors on ET-1 gene transcription and the consequent decrease in ET-1 mRNA expression in the cultured vascular endothelial cells. These findings suggest that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ET-1-related cardiovascular diseases, probably through the activation of NF-kappaB, and also that the use of proteasome inhibitors may be a novel approach to the treatment of cardiovascular diseases.
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PMID:Pathophysiological role of proteasome-dependent proteolytic pathway in endothelin-1-related cardiovascular diseases. 1532 Aug 49


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