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)

The present study was undertaken to elucidate the G-protein and mitogen-activated kinase (MAP kinase) coupled signaling profile in a genetic model of hypertension and congestive heart failure (CHF) that mimics similar disease in humans. At the receptor level, Ang II type 1 receptor (AT1R) increased in left ventricular hypertrophy (LVH) and reverted to normal in CHF, whereas there was a downregulation of the Ang II type 2 receptor (AT2R) in CHF. At the transducer level, Galphaq and Galpha12 protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, Gbeta and Galpha13 protein content were markedly upregulated in CHF. Furthermore, using phospho-specific antibodies in Western blots and in vitro kinase assays, we found at the effector level an upregulation of the small G-protein Rac1 activity during LVH but a decrease during CHF. In parallel, small G-protein Rho activity was significantly increased during LVH but was unchanged in failure. We found at the downstream level that MAP kinase isoforms extracellular signal regulated-kinase (ERK1/2), big mitogen-activated kinase (BMK1/ERK5), C-jun N-terminal-activated kinase (JNKs/SAPKs), and stress-activated kinase (p38) bioactivities were increased during LVH. During CHF, ERK1/2 and JNK1/2 kinase activities were decreased, whereas BMK1/ERK5 kinase activity reverted to normal values. In conclusion, this study demonstrates, for the first time, multistep alterations of G-protein and MAP kinase signaling pathways in LVH and progression to failure in a genetic model of hypertension and failure.
Hypertension 2003 Apr
PMID:Alterations in G protein and MAP kinase signaling pathways during cardiac remodeling in hypertension and heart failure. 1264 4

Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al. FASEB J. 2000;15:261-270). The current study was designed to investigate molecular mechanisms of mechanical stretch-induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I-coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin beta1 containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional Rac completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin beta1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a beta1-integrin-blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a beta1-integrin-blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress-induced apoptosis in vascular smooth muscle cells is mediated by beta1-integrin-rac-p38-p53 signaling pathways.
Hypertension 2003 Apr
PMID:Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta1-integrin signaling pathways. 1264 6

Endothelin (ET), derived from the endothelium of blood vessels, is a potent vasoactive peptide. Although it has been reported to be involved in cardiovascular diseases, such as hypertension, the mechanism by which ET evokes vasoconstriction is still unclear. On the other hand, p42/p44 mitogen-activated protein kinase (MAPK) and p38 MAPK are activated by a variety of growth factors and cellular stresses, respectively. However, the role of p42/p44 MAPK and p38 MAPK on the ET-1-induced vasoconstriction is not fully understood. This study was undertaken to determine whether p42/p44 MAPK and p38 MAPK participate in the regulation of vascular smooth muscle contraction by ET-1. The isometric vasoconstriction and intracellular Ca(2+) ([Ca(2+)](i)) were simultaneously measured using CAF-100. Phosphorylation of myosin light chain (MLC) and p42/p44 MAPK, p38 MAPK were determined by Western blots. In rat thoracic aorta, ET-1 induced a sustained contraction. In contrast, [Ca(2+)](i) was decreased with time. Both PD98059, an inhibitor of p42/p44 MAPK, and SB203580, an inhibitor of p38 MAPK, partially attenuated ET-1-induced contractions in concentration-dependent manners. ET-1 increased phosphorylation of both p42/p44 MAPK and p38 MAPK, and PD98059 and SB203580 completely decreased phosphorylation of p42/p44 MAPK and p38 MAPK in response to ET-1 stimulation, respectively. On the other hand, PD98059 and SB203580 did not affect MLC phosphorylation in response to ET-1 stimulation. These results indicate that p38 MAPK, as well as p42/p44 MAPK, may partially regulate the ET-1-induced contraction through a MLC phosphorylation-independent pathway.
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PMID:Mitogen-activated protein kinases partially regulate endothelin-1-induced contractions through a myosin light chain phosphorylation-independent pathway. 1265 18

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in restricted subpopulations of cells. High levels of expression can be detected in the macula densa (MD) and associated cortical thick ascending limb of Henle (cTALH) cells and medullary interstitial cells (MICs). In human biopsy specimens, COX-2 expression is also detected in glomerular podocytes and increased podocyte expression is seen in experimental models of progressive glomerular injury. Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension) and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide (NO) generated by neuronal nitric oxide synthase (nNOS) is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 MAP kinase activity and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression in MICs increases in response to a high-salt diet, as well as water deprivation. Studies in cultured MICs confirm that expression is increased in response to hypertonicity, and expression is mediated at least in part by nuclear factor-kappaB (NFkappaB) activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and following water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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PMID:Cyclooxygenase-2 and the kidney: functional and pathophysiological implications. 1268 21

Mitogen-activated protein kinases (MAP kinases), including extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38, play a central role in cellular responses by various stress stimuli such as cell proliferation, apoptosis, migration, or gene expression. Furthermore, activator protein-1 (AP-1), a transcription factor which can be activated by MAP kinases, also is involved in a variety of celllar responses, as well as MAP kinases. MAP kinases and AP-1 are significantly activated in vascular tissues by hypertension, angiotensin II, or balloon injury. We have made dominant negative mutants of MAP kinases or c-Jun, to specifically inhibit in vivo activation of MAP kinases or AP-1. Vascular gene transfer of each dominant negative mutant of MAP kinases or c-Jun prevents intimal hyperplasia after balloon injury, which is associated with the inhibition of smooth muscle cell proliferation in the intima and the media and probably also associated with inhibition of smooth muscle cell migration. However, in vitro findings on cultured vascular smooth muscle cells suggest that the molecular mechanism underlying inhibition of intimal hyperplasia may be different among each dominant negative mutant of MAP kinases and c-Jun. MAP kinases and c-Jun seem to be the promising therapeutic target for vascular remodeling.
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PMID:Stress and vascular responses: mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. 1268 38

Reactive oxygen species (ROS) play a role in cardiovascular diseases such as heart failure and hypertension. Furthermore, increasing evidence has accumulated suggesting that ROS can also be formed subsequent to the stimulation of various receptors, thus functioning as second messengers. The objective of the present study was to elucidate the role of intracellular-generated ROS in the inotropic and chronotropic effects of the alpha1- and beta-adrenoceptor and the ET-receptor stimulation in isolated rat atria. In addition, we investigated whether the MAPKerk pathway is involved in the ROS-provoked rise of contractile force. For this purpose hydrogen peroxide was applied, which is known to serve several endogenous functions as a second messenger. Moreover, hydrogen peroxide readily crosses cell membranes, which thus allows to mimic the intracellular formation. Preincubation of atria with EUK 8 (400 microM), a cell permeable superoxide dismutase- and catalase-mimetic, reduced the positive inotropic effect upon alpha1-adrenoceptor and ET-receptor stimulation. The responsiveness to beta-adrenoceptor stimulation remained unaffected by this pretreatment. The chronotropic effects were not altered by preincubation with EUK 8. In contrast to the MAPK(p38) inhibitor SB203580 (2 and 10 microM), the two MKKmek inhibitors PD98059 (30 and 100 microM) and U0126 (10 microM) significantly attenuated the positive inotropic response to hydrogen peroxide in isolated rat left atria. In addition, inhibition of the Na+/H+ exchange (NHE) by cariporide (1 microM) counteracted ROS-provoked increase of contractile force. From the present study we conclude that the inotropic responses to alpha1-adrenoceptor and ET-receptor stimulation are, at least partially, caused by intracellular-formed ROS, that subsequently may activate the MAPKerk pathway and the NHE.
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PMID:The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation. 1273 26

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.
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PMID:Hypertension accelerates diabetic nephropathy in Wistar fatty rats, a model of type 2 diabetes mellitus, via mitogen-activated protein kinase cascades and transforming growth factor-beta1. 1273 3

Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.
Hypertension 2003 Jun
PMID:Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. 1274 10

In hearts with chronic left ventricular (LV) systolic dysfunction secondary to hypertension or myocardial infarction, MAPK phosphorylation and/or activity are increased. Whether other settings of LV dysfunction not associated with ischemia-reperfusion are also characterized by increased MAPK phosphorylation or activity is unknown. After 3 wk of rapid LV pacing (400 beats/min), eight rabbits displayed clinical signs of heart failure (HF), and echocardiography revealed an increase in LV end-diastolic diameter from 15.6 +/- 0.7 (means +/- SE) to 18.8 +/- 0.7 mm and a reduced shortening fraction from 31 +/- 1to10 +/- 2% (both P < 0.05). Morphological alterations in HF included increased numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cardiomyocytes, extent of fibrosis, and cross-sectional cardiomyocyte area. Total p38 MAPK did not differ between failing and normal hearts (n = 8). However, p38 MAPK phosphorylation [164,488 +/- 29,323 vs. 43,565 +/- 14,817 arbitrary units (AU), P < 0.05, densitometry] and the activities of p38 MAPK-alpha and -beta were increased in failing compared with normal hearts (149,441 +/- 38,381 and 170,430 +/- 32,952 vs. 68,815 +/- 28,984 and 81,788 +/- 22,774 AU, respectively, both P < 0.05). In failing compared with normal hearts, total and phosphorylated JNK46 and JNK54 MAPK were increased, whereas total and phosphorylated ERK MAPK remained unchanged. In pacing-induced HF, p38 and JNK MAPK phosphorylation as well as p38 MAPK activity was increased. Further studies will have to define whether or not chronic specific blockade of MAPK activity can interfere with apoptosis/fibrosis and thereby attenuate the progression of HF.
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PMID:Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits. 1284 18

The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-beta1 (TGF-beta1) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-beta1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-beta1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-beta1 levels, whereas the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-beta1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-beta1 and NO in both strains, production of TGF-beta1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-beta1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.
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PMID:The interrelationship between TGF-beta1 and nitric oxide is altered in salt-sensitive hypertension. 1286 56


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