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)

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

Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day -7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-beta expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-beta and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1-mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.
Hypertension 2004 Feb
PMID:Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis. 1469

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

Myocardial remodeling is an adaptive response of the myocardium to several forms of stress culminating in cardiac fibrosis, left ventricular dilation, and loss of contractility. The remodeling processes of the extracellular matrix are controlled by matrix metalloproteinases, which are in turn regulated by growth factors and inflammatory cytokines. The inflammatory transcription factor nuclear factor kappaB has been implicated in the transcriptional regulation of several matrix metalloproteinases. Because activation of nuclear factor kappaB in turn is essentially controlled by the ubiquitin-proteasome system, we investigated the hypothesis that inhibition of the proteasome may prevent activation of matrix metalloproteinases. We demonstrate here that inhibition of the proteasome in rat cardiac fibroblasts suppressed not only expression of matrix metalloproteinases 2 and 9, but also expression of collagen Ialpha1, Ialpha2, and IIIalpha1 as determined by in-gel zymography and real-time reverse transcription-polymerase chain reaction. Moreover, myocardial expression of matrix metalloproteinases and collagens was effectively suppressed by systemic treatment of spontaneously hypertensive rats over 12 weeks with the proteasome inhibitor MG132, which resulted in a marked reduction of cardiac fibrosis (-38%) compared with control animals. We conclude that inhibition of the ubiquitin-proteasome system may provide a new and attractive tool to interfere with collagen and matrix metalloproteinase expression, and therefore might be of possible use in the therapy of myocardial remodeling.
Hypertension 2004 Oct
PMID:Downregulation of matrix metalloproteinases and collagens and suppression of cardiac fibrosis by inhibition of the proteasome. 1533 35

It was reported that angiotensin-converting enzyme (ACE) plays an important role in increasing blood pressure. Recently, it was reported that several food hydrolysates have ACE inhibitory effects in the spontaneous hypertensive rat (SHR) model and mildly hypertensive subjects. Therefore, the anti-hypertensive effects of brewer's yeast BY-G were investigated, which contains many kinds of beneficial nutrients (vitamins, minerals, nucleic acids, glutathione, amino acids, etc.). The aim of this study was to evaluate the anti-hypertensive effects of BY-G and its component peptides obtained by enzymatic treatment. The peptide fraction KRF814 was obtained by the hydrolysate of BY-G with alkaline protease and then treated with Amberlite XAD-2. The KRF814, which has an inhibitory effect on ACE in vitro, was obtained. BY-G and KRF814 were fed to male SHR and showed significantly anti-hypertensive effects. KRF814 contained alanyl-phenylalanine (AF) and glycyl-phenylalanine (GF), which significantly decreased systolic BP in the SHR model. The active ingredients of KRF814, AF, and GF had about 60% of the potency of the positive control, which was captopril. It is considered that intake of BY-G or its component peptides as a functional food stuff might be beneficial for improving BP in people with hypertension.
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PMID:A yeast extract high in bioactive peptides has a blood-pressure lowering effect in hypertensive model. 1637 2

Immuno-proteasome is thought to be responsible for the processing of intracellular antigens and is induced when cells are treated with the inflammatory cytokines promoting cellular immunity. We tested the possibility that immuno-proteasome can be up-regulated in renal cells exposed to a long-lasting ischemia and inflammation in an experimental model of two-kidney, one-clip renovascular hypertension in the rat. Western blotting showed that immuno-proteasome subunit, LMP7, was up-regulated in the clipped ischemic kidney that was atrophic, but not in the contralateral unclipped kidney that underwent compensatory hypertrophy. Immunohistochemical analysis revealed that LMP7 was highly expressed in cortical epithelial and endothelial cells of the ischemic kidney. Surprisingly, the second immuno-subunit, LMP2, was almost undetectable, indicating that renal ischemia may induce exclusively the LMP7 subunit. We also found that renal ischemia neither reduced the SDS-stimulated proteasomal activity nor affected a high level of the PA28 activator. Thus, the results provide evidence that LMP7 immuno-subunit is induced in renal cells exposed to a long-lasting renal ischemia and inflammation, and that there is a direct link between LMP induction and renal atrophy. This opens an opportunity to study a role for LMP-containing proteasomes in the kidneys and other organs undergoing reduction in mass in diseases accompanied by a long-lasting ischemia and inflammatory responses.
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PMID:Immuno-proteasome subunit LMP7 is up-regulated in the ischemic kidney in an experimental model of renovascular hypertension. 1676 38

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
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PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60

Whether morning blood pressure surge influences the molecular mechanisms of plaque progression toward instability is not known. Recently, we have demonstrated enhanced activity of the ubiquitin-proteasome system in human plaques and evidenced that it is associated with inflammatory-induced plaque rupture. We evaluated the inflammatory infiltration and ubiquitin-proteasome activity in asymptomatic carotid plaques of hypertensive patients with different patterns of morning blood pressure surge. Plaques were obtained from 32 hypertensive patients without morning blood pressure surge and 28 with morning blood pressure surge enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T-lymphocytes, human leukocyte antigen-DR+cells, ubiquitin-proteasome activity, nuclear factor-kappaB, inhibitor kB-beta, tumor necrosis factor-alpha, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques obtained from hypertensive patients without morning blood pressure surge, plaques from with morning blood pressure surge had more macrophages, T-lymphocytes, human leukocyte antigen-DR+cells (P<0.001), ubiquitin-proteasome activity, tumor necrosis factor-alpha, nuclear factor-kB (P<0.001), nitrotyrosine, and matrix metalloproteinase-9 (P<0.01), along with a lesser collagen content and IkB-beta levels (P<0.001). Enhanced ubiquitin-proteasome activity in atherosclerotic lesions of patients with morning blood pressure surge is associated with inflammatory-dependent unstable plaque phenotype. These data suggest a potential interplay between morning blood pressure surge and ubiquitin-proteasome activity in atherosclerosis pathophysiology.
Hypertension 2007 Apr
PMID:Morning blood pressure surge as a destabilizing factor of atherosclerotic plaque: role of ubiquitin-proteasome activity. 1732 33


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