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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein (MAP) kinase cascades are major signaling systems by which cells transduce extracellular cues into intracellular responses. In general, MAP kinases are activated by phosphorylation on tyrosine and threonine residues and inactivated by dephosphorylation. Therefore, MAP kinase phosphatase-1 (MKP-1), a dual-specificity protein tyrosine phosphatase that exhibits catalytic activity toward both regulatory sites on MAP kinases, is suggested to be responsible for the downregulation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK), and p38 MAP kinase. In the present study, we examined the role of these MAP kinases in the induction of MKP-1 in vascular smooth muscle cells (VSMCs). Extracellular stimuli such as platelet-derived growth factor (PDGF), 12-O-tetradecanoylphorbol 13-acetate (TPA), and angiotensin II, which activated ERK but not SAPK/p38 MAP kinase, induced a transient induction of MKP-1 mRNA and its intracellular protein. In addition, PD 098059, an antagonist of MEK (MAP kinase/ERK kinase), the upstream kinase of ERK, significantly reduced the PDGF-induced activation of ERK and potently inhibited the expression of MKP-1 after stimulation with PDGF, thereby demonstrating the induction of MKP-1 in response to activation of the ERK signaling cascade. Furthermore, anisomycin, a potent stimulus of SAPK and p38 MAP kinase, also induced MKP-1 mRNA expression. This effect of anisomycin was significantly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. These data suggest the induction of MKP-1, not only after stimulation of the cell growth promoting ERK pathway but also in response to activation of stress-responsive MAP kinase signaling cascades. We suggest that this pattern of MKP-1 induction may be a negative feedback mechanism in the control of MAP kinase activity in VSMCs.
Hypertension 1998 Oct
PMID:Regulation of mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle cells. 977 60

The concept of pharmacomechanical coupling, introduced 30 years ago to account for physiological mechanisms that can regulate contraction of smooth muscle independently of the membrane potential, has since been transformed from a definition into what we now recognize as a complex of well-defined, molecular mechanisms. The release of Ca2+ from the SR by a chemical messenger, InsP3, is well known to be initiated not by depolarization, but by agonist-receptor interaction. Furthermore, this G-protein-coupled phosphatidylinositol cascade, one of many processes covered by the umbrella of pharmacomechanical coupling, is part of complex and general signal transduction mechanisms also operating in many non-muscle cells of diverse organisms. It is also clear that, although the major contractile regulatory mechanism of smooth muscle, phosphorylation/dephosphorylation of MLC20, is [Ca2+]-dependent, the activity of both the kinase and the phosphatase can also be modulated independently of [Ca2+]i. Sensitization to Ca2+ is attributed to inhibition of SMPP-1M, a process most likely dominated by activation of the monomeric GTP-binding protein RhoA that, in turn, activates Rho-kinase that phosphorylates the regulatory subunit of SMPP-1M and inhibits its myosin phosphatase activity. It is likely that the tonic phase of contraction activated by a variety of excitatory agonists is, at least in part, mediated by this Ca(2+)-sensitizing mechanism. Desensitization to Ca2+ can occur either through inhibitory phosphorylation of MLCK by other kinases or autophosphorylation and by activation of SMPP-1M by cyclic nucleotide-activated kinases, probably involving phosphorylation of a phosphatase activator. Based on our current understanding of the complexity of the many cross-talking signal transduction mechanisms that operate in cells, it is likely that, in the future, our current concepts will be refined, additional mechanisms of pharmacomechanical coupling will be recognized, and those contributing to the pathologenesis diseases, such as hypertension and asthma, will be identified.
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PMID:Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. 1008 10

We here review mechanisms that can regulate the activity of myosin II, in smooth muscle and non-muscle cells, by modulating the Ca2+ sensitivity of myosin regulatory light chain (RLC) phosphorylation. The major mechanism of Ca2+ sensitization of smooth muscle contraction and non-muscle cell motility is through inhibition of the smooth muscle myosin phosphatase (MLCP) that dephosphorylates the RLC in smooth muscle and non-muscle. The active, GTP-bound form of the small GTPase RhoA activates a serine/threonine kinase, Rho-kinase, that phosphorylates the regulatory subunit of MLCP and inhibits phosphatase activity. G-protein-coupled release of arachidonic acid may also contribute to inhibition of MLCP acting, at least in part, through the Rho/Rho-kinase pathway. Protein kinase C(s) activated by phorbol esters and diacylglycerol can also inhibit MLCP by phosphorylating and thereby activating CPI-17, an inhibitor of its catalytic subunit; this mechanism is independent of the Rho/Rho-kinase pathway and plays only a minor, transient role in the G-protein-coupled mechanism of Ca2+ sensitization. Ca2+ sensitization by the Rho/Rho-kinase pathway contributes to the tonic phase of agonist-induced contraction in smooth muscle, and abnormally increased activation of myosin II by this mechanism is thought to play a role in diseases such as high blood pressure and cancer cell metastasis.
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PMID:Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. 1063 96

We have shown that interleukin-1beta (IL-1beta) activates the human brain natriuretic peptide (hBNP) promoter via a transcriptional mechanism. Others have reported that changes in intracellular calcium (Ca(2+)) mediate the action of IL-1beta. We questioned whether Ca(2+) and Ca(2+)-dependent pathways mediate IL-1beta regulation of the hBNP promoter in cardiac myocytes. The hBNP promoter (-1818 to +100) coupled to a luciferase cDNA reporter gene was transferred into neonatal cardiac myocytes. Cells were then treated with agents that modify Ca(2+) levels or inhibit Ca(2+)-dependent kinases, and luciferase activity was measured as an index of hBNP promoter activity. The Ca(2+) ionophore A23187 increased hBNP promoter activity; however, neither EGTA nor nifedipine reduced IL-1beta-stimulated promoter activity. Long-term treatment with thapsigargin, which depletes intracellular Ca(2+) stores, decreased basal promoter activity and blocked the effect of IL-1beta. Inhibition of protein kinase C completely blocked IL-1beta-stimulated hBNP promoter activity, whereas inhibition of Ca(2+)/calmodulin-dependent kinase II decreased promoter activity by 40%. In contrast, inhibition of the Ca(2+)-regulated phosphatase calcineurin by cyclosporin A had no effect. These data suggest that (1) Ca(2+) activates the hBNP promoter; (2) release of Ca(2+) from intracellular stores is important to IL-1beta regulation of the hBNP promoter, but transport via voltage-sensitive Ca(2+) channels is not; (3) protein kinase C and Ca(2+)/calmodulin-dependent kinase II mediate the action of IL-1beta; and (4) the phosphatase calcineurin is not involved in IL-1beta regulation of the hBNP promoter. Thus, Ca(2+) and Ca(2+)-dependent pathways are critical to IL-1beta regulation of the hBNP promoter.
Hypertension 2000 Jan
PMID:Interleukin-1beta regulates the human brain natriuretic peptide promoter via Ca(2+)-dependent protein kinase pathways. 1064 13

Mechanical force is an important modulator of cellular morphology and function in a variety of tissues, and is particularly important in cardiovascular systems. Vascular smooth muscle cell (VSMC) hypertrophy and proliferation contribute to the development of atherosclerosis, hypertension, and restenosis, where mechanical forces are largely disturbed. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. Recently, it has been demonstrated that mechanical stress rapidly induced phosphorylation of platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once mechanical force is sensed, protein kinase C and mitogen-activated protein kinases (MAPKs) were activated, leading to increased c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. Interestingly, physical forces also rapidly resulted in expression of MAPK phosphatase-1 (MKP-1), which inactivates MAPKs. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signalling pathways, usually used by growth factors. These findings have significantly enhanced our knowledge of the pathogenesis of arteriosclerosis and provided promising information for therapeutic interventions for vascular diseases.
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PMID:Mechanical stress-initiated signal transductions in vascular smooth muscle cells. 1098 77

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

Chronic stimulation of the renin-angiotensin system induces an elevation of blood pressure and the development of cardiac hypertrophy via the actions of its effector, angiotensin II. In cardiomyocytes, mitogen-activated protein kinases as well as protein kinase C isoforms have been shown to be important in the transduction of trophic signals. The Ca(2+)/calmodulin-dependent phosphatase calcineurin has also been suggested to play a role in cardiac growth. In the present report, we investigate possible cross-talks between calcineurin, protein kinase C, and mitogen-activated protein kinase pathways in controlling angiotensin II-induced hypertrophy. Angiotensin II-stimulated cardiomyocytes and mice with angiotensin II-dependent renovascular hypertension were treated with the calcineurin inhibitor cyclosporin A. Calcineurin, protein kinase C, and mitogen-activated protein kinase activations were determined. We show that cyclosporin A blocks angiotensin II-induced mitogen-activated protein kinase activation in cultured primary cardiomyocytes and in the heart of hypertensive mice. Cyclosporin A also inhibits specific protein kinase C isoforms. In vivo, cyclosporin A prevents the development of cardiac hypertrophy, and this effect appears to be independent of hemodynamic changes. These data suggest cross-talks between the calcineurin pathway, the protein kinase C, and the mitogen-activated protein kinase signaling cascades in transducing angiotensin II-mediated stimuli in cardiomyocytes and could provide the basis for an integrated model of cardiac hypertrophy.
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PMID:Calcineurin blockade prevents cardiac mitogen-activated protein kinase activation and hypertrophy in renovascular hypertension. 1101 40

Acute Fatty Liver of Pregnancy. The acute fatty liver of pregnancy (AFLP) is an uncommon entity, potentially fatal, which affects women during the last quarter of pregnancy. It is characterized by a prodromic period of symptoms followed by jaundice, hepatic failure, clotting disorders and fatty infiltration of the liver, evident through hepatic biopsy. The incidence ranks from 1 to 20 thousand births, and it is more frequent among women with multiple pregnancies. We report the case of a 29-year-old patient, with multiple pregnancy 33 to 34 weeks of gestation, blood pressure values of 140/90 mmHg, 160,000/dL platelets, PT 25.6 seconds, TPT 64.7 seconds, blood glucose 52 mL/dL, creatinine 2.1 mg/dL, uric acid 11.9 mg/dL, lactic dihydrogenase 1063 U/l, GPT 220 U/l, AF 1172 U/l, total bilirubin 8.4 mg/dL, proteinuria 30 mg/dL. A cesarean section was practiced after correcting the coagulation disorders. The first twin was a male with birth weight of 2,070 g, APGAR 8-9; the second twin was a female fetal death weighting 2,050 g. Hepatic biopsy confirmed the diagnosis. The cause of AFLP is unknown. The frequency among multiple pregnancies is higher. Almost half of the cases have hypertension and proteinuria. There are also high levels of both transaminases, phosphatase and bilirubins and hypoglycemia. The prothrombin time is enlarged. The differential diagnostic between pre-eclampsia and AFLP is not crucial since the obstetric management is the same. The main treatment is promptly deliverance and general measures. The obstetrician must be aware of this hepatic disease.
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PMID:[Acute fatty liver of pregnancy. Report of a case and review of the literature]. 1119 62

Cardiomyocytes bind, internalize, and activate recombinant human prorenin through mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptors. To investigate whether this also applies to native human prorenin, neonatal rat myocytes were incubated for 4 hours at 37 degrees C with various prorenin-containing human body fluids. Uptake and activation by M6P/IGFII receptors were observed for plasma prorenin from subjects with renal artery stenosis and/or hypertension and for follicular fluid prorenin. The total amount of cellular renin and prorenin (expressed as percentage of the levels of renin and prorenin in the medium) after 4 hours of incubation was 4 to 10 times lower than after incubation with recombinant human prorenin. Although plasma contains alkaline phosphatases capable of inactivating the M6P label as well as soluble M6P/IGFII receptors that block prorenin binding in a competitive manner and proteins (eg, insulin, IGFII) that increase the number of cell-surface M6P/IGFII receptors, these factors were not responsible for the modest uptake of native human prorenin. Uptake did not occur during incubation of myocytes with plasma prorenin from anephric subjects or with amniotic fluid prorenin, and this was not due to the presence of excessively high levels of M6P/IGFII receptors and/or phosphatase activity in these fluids. In conclusion, myocytes are capable of binding, internalizing, and activating native human prorenin of renal and ovarian origin through M6P/IGFII receptors. Differences in prorenin glycosylation and/or phosphorylation as well as the concentration of soluble M6P/IGFII receptors and growth factors affecting cell-surface M6P/IGFII receptor density determine the amount of prorenin entering the heart and thus cardiac angiotensin II production.
Hypertension 2001 Feb
PMID:Cardiomyocytes bind and activate native human prorenin : role of soluble mannose 6-phosphate receptors. 1123 Mar 61

The small G protein Rho and its target Rho-kinase may participate in the mechanisms underlying vascular contractile tone via inhibition of myosin light chain phosphatase. The present study has tested the hypothesis that Rho-kinase activity normally contributes to cerebral vascular tone in vivo, and that this effect is augmented during chronic hypertension. Comparative studies also examined the role of protein kinase C (PKC) in regulation of cerebral artery tone. Two Rho-kinase inhibitors, Y-27632 (0.1 to 100 micromol/L) and HA1077 (1 to 10 micromol/L), caused marked concentration-dependent increases in basilar artery diameter of anesthetized normotensive rats (Sprague-Dawley and Wistar-Kyoto [WKY] strains), as measured using a cranial window approach. By comparison, the selective PKC inhibitors calphostin C (0.01 to 0.5 micromol/L) and Ro 31-8220 (5 micromol/L) had little or no effect on basilar artery diameter. Vasodilator responses to Y-27632 were unaffected by PKC inhibition or activation. In two models of chronic hypertension (spontaneously hypertensive rats and WKY rats treated with N-nitro-L-arginine methyl ester for 4 weeks), Y-27632 elicited cerebral vasodilator responses that were significantly greater than in control WKY rats (P<0.05), indicating that the chronically hypertensive state and not genetic factors contributed to the increased responses to Rho-kinase inhibition. PKC inhibition had no significant effect on basilar artery diameter in chronically hypertensive rats. These data suggest that Rho-kinase, but not PKC, activity contributes substantially to cerebral artery tone in vivo, and this effect is augmented in the cerebral circulation during chronic hypertension.
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PMID:Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C. 1132 68


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