Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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.
 ...
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.
 ...
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

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11beta-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type 11beta-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type 11beta-HSD2 occurs through the proteasome pathway. Therefore, impaired 11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.
 ...
PMID:Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess. 1731 22

Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using (3)H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 micromol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 micromol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 micromol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 micromol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 micromol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.
Hypertension 2007 Oct
PMID:Aldosterone suppresses insulin signaling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. 1764 73

RGS2, a GTPase-activating protein (GAP) for G(q)alpha, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type Ialpha cGMP-dependent protein kinase (cGKIalpha), increasing its GAP activity. To understand how RGS2 and cGKIalpha regulate vascular smooth muscle signaling and function, we identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates RGS2. We show that RGS2 regulates vasoconstrictor-stimulated Ca(2+) store release, capacitative Ca(2+) entry, and noncapacitative Ca(2+) entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase Cbeta activation, Ca(2+) store release, and capacitative Ca(2+) entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKIalpha phosphorylation sites in RGS2 does not stabilize the protein, suggesting that cGK activity regulates RGS2 degradation by other mechanisms. cGK activation promotes association of RGS2 with the plasma membrane by a mechanism requiring its cGKIalpha phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIalpha therefore may control a cycle of RGS2 activation and inactivation. By diminishing cGK activity, endothelial dysfunction may impair RGS2 activation, thereby blunting vascular relaxation and contributing to hypertension.
 ...
PMID:Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. 1768 44

We have reviewed the impact of the ubiquitin proteasome system (UPS) on atherosclerosis progression of diabetic patients. A puzzle of many pieces of evidence suggests that UPS, in addition to its role in the removal of damaged proteins, is involved in a number of biological processes including inflammation, proliferation and apoptosis, all of which constitute important characteristics of atherosclerosis. From what can be gathered from the very few studies on the UPS in diabetic cardiovascular diseases published so far, the system seems to be functionally active to a different extent in the initiation, progression, and complication stage of atherosclerosis in the diabetic people. Further evidence for this theory, however, has to be given, for instance by specifically targeted antagonism of the UPS. Nonetheless, this hypothesis may help us understand why diverse therapeutic interventions, which have in common the ability to reduce ubiquitin-proteasome activity, can impede or delay the onset of diabetes and cardiovascular diseases (CVD). People with type 2 diabetes are disproportionately affected by CVD, compared with those without diabetes 1. The prevalence, incidence, and mortality from all forms of CVD (myocardial infarction, cerebro-vascular disease and congestive heart failure) are strikingly increased in persons with diabetes compared with those withoutdiabetes 2. Furthermore, diabetic patients have not benefited by the advances in the management of obesity, dyslipidemia, and hypertension that have resulted in a decrease in mortality for coronary heart disease (CHD) patients without diabetes 3. Nevertheless, these risk factors do not fully explain the excess risk for CHD associated with diabetes 45. Thus, the determinants of progression of atherosclerosis in persons with diabetes must be elucidated. Beyond the major risk factors, several studies have demonstrated that such factors, strictly related to diabetes, as insulin-resistance, post-prandial hyperglycemia and chronic hyperglycemia play a role in the atherosclerotic process and may require intervention 67. Moreover, it is important to recognize that these risk factors frequently "cluster" inindividual patients and possibly interact with each other, favouring the atherosclerosis progression toward plaque instability. Thus, a fundamental question is, "which is the common soil hypothesis that may unifying the burden of all these factors on atherosclerosis of diabetic patients? Because evidences suggest that insulin-resistance, diabetes and CHD share in common a deregulation of ubiquitin-proteasome system (UPS), the major pathway for nonlysosomal intracellular protein degradation in eucaryotic cells 89, in this review ubiquitin-proteasome deregulation is proposed as the common persistent pathogenic factor mediating the initial stage of the atherosclerosis as well as the progression to complicated plaque in diabetic patients.
 ...
PMID:The possible role of the ubiquitin proteasome system in the development of atherosclerosis in diabetes. 1797 Dec 5

Inhibitors of the proteasome interfere with transcriptional regulation of growth signaling pathways and block cell cycle progression of mitotic cells. As growth signaling pathways are highly conserved between mitotic and postmitotic cells, we hypothesized that proteasome inhibition might also be a valuable approach to interfere with hypertrophic growth of postmitotic cardiomyocytes. To test this hypothesis, we analyzed the effects of proteasome inhibition on hypertrophic growth of neonatal rat cardiomyocytes. Partial inhibition of the proteasome effectively suppressed cardiomyocyte hypertrophy as determined by reduced cell size, inhibition of hypertrophy-mediated induction of RNA and protein synthesis, reduced expression of several hypertrophic marker genes, and diminished transcriptional activation of the BNP promotor. Importantly, suppression of hypertrophic growth was independent of the hypertrophic agonist used. Expressional profiling and subsequent Western blot and kinase assays revealed that proteasome inhibition induced a cellular stress response with reduced expression of conserved growth signaling mediators and impaired G1/S phase transition of cardiomyocytes. In hypertensive Dahl-salt sensitive rats, inhibition of the proteasome with low doses of the FDA approved proteasome inhibitor Velcade significantly reduced hypertrophic heart growth. Our data provide important insight into the suppressive effects of proteasome inhibitors on hypertrophic growth of cardiomyocytes and establish low-dose proteasome inhibition as a new and broad-spectrum approach to interfere with cardiac hypertrophy.
Hypertension 2008 Feb
PMID:Suppression of cardiomyocyte hypertrophy by inhibition of the ubiquitin-proteasome system. 1808 45

Renal sodium transport is increased by the angiotensin type 1 receptor (AT(1)R), which is counterregulated by dopamine via unknown mechanisms involving either the dopamine type 1 (D(1)R) or dopamine type 5 receptor (D(5)R) that belong to the D(1)-like receptor family of dopamine receptors. We hypothesize that the D(1)R and D(5)R differentially regulate AT(1)R protein expression and signaling, which may have important implications in the pathogenesis of essential hypertension. D(1)R and D(5)R share the same agonists and antagonists; therefore, the selective effects of either D(1)R or D(5)R stimulation on AT(1)R expression in human renal proximal tubule cells were determined using antisense oligonucleotides selective to either D(1)R or D(5)R. We also determined the role of receptor tyrosine kinase and the proteosome on the D(1)R/D(5)R-mediated effects on AT(1)R expression and internalization. In renal proximal tubule cells, D(5)R (not D(1)R) decreased AT(1)R expression (half-life: 0.47+/-0.18 hours) and AT(1)R-mediated extracellular signal-regulated kinase 1/2 phosphorylation (232+/-18.9 U with angiotensin II [10(-7) mol/L] versus 81+/-8.9 U with angiotensin II [10(-7) mol/L] and fenoldopam [D(1)R/D(5)R agonist; 10(-6) mol/L; P<0.05; n=6). The fenoldopam-induced decrease in AT(1)R expression was reversed by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo (3,4-d) pyrimidine (c-Src tyrosine-kinase inhibitor) and clasto-lactacystin beta-lactone (proteasome inhibitor), demonstrating that the fenoldopam-mediated decrease in total cell AT(1)R expression is a result of a c-Src- and proteasome-dependent process. D(5)R stimulation decreases AT(1)R expression and is c-Src and proteasome dependent. The discovery of differential regulation by D(1)R and D(5)R opens new avenues for the development of agonists selective to either receptor subtype as targeted antihypertensive agents that can decrease AT(1)R-mediated antinatriuresis.
Hypertension 2008 Feb
PMID:Differential D1 and D5 receptor regulation and degradation of the angiotensin type 1 receptor. 1817 57


<< Previous 1 2 3 4 5 6 7 8 9 Next >>