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

The effect of hypertension on spinal induction of the c-fos proto-oncogene following noxious mechanical stimulation of the skin was studied in the rat. The occlusion of renal artery raised blood pressure steeply, reaching 52% over initial values. Oral administration of NG-nitro-L-arginine methyl ester provoked a gradual increase in blood pressure which reached up to 62%. The numbers of spinal dorsal horn Fos-immunoreactive nuclei were reduced to 66% and 38% of controls in animals with renal- and pharmacologically-induced hypertension, respectively. These data indicate that hypertension is accompanied by an inhibition of spinal nociceptive neurones which probably accounts for the hypoalgesia observed in hypertensive subjects. They further suggest an influence by the rate of increase of blood pressure on the level of spinal inhibition.
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PMID:Hypertension inhibits noxious-evoked c-fos expression in the rat spinal cord. 852 37

The prevalence of hypertension and atherosclerosis among subjects with hyperinsulinemia supports the premise of a direct metabolic link between insulin and angiotensin II at the cellular level. In the present study, the effect of insulin on the angiotensin II-induced growth of A10 smooth muscle cells (SMC) was investigated. Treatment of quiescent A10 cells with angiotensin II caused an increase in RNA synthesis, proto-oncogene c-fos mRNA levels and cell size dependent upon pretreatment with insulin. The insulin requirement was independent of its actions as a growth factor, since a pre-treatment of at least 24 h with insulin was essential for growth stimulation by angiotensin II. Using RT-PCR, insulin was shown to regulate AT2 receptor expression in both quiescent and differentiating cells. These data suggest the AT2 receptor, which mediates the growth effects of angiotensin II in A10 cells, may be the critical target for the effect of insulin.
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PMID:Insulin is required for angiotensin II-mediated hypertrophy of smooth muscle cells. 889 51

In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. Angiotensin II was isolated by virtue of its vasoconstrictor abilities and has long been thought to play a critical role in hypertension. However, recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure. The expanding role of angiotensin II indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60(c-src) kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-gamma after angiotensin II stimulation. These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases. 913 Apr 41

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis and congestive heart failure. The expanding role of angiotensin II implies that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Recent data show that angiotensin II stimulates not only cytoplasmic tyrosine kinases including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as Axl and PDGF by as yet undefined autocrine/paracrine mechanisms. Finally, tyrosine kinases, which mediate tyrosine phosphorylation of key signal mediators such as Shc, Raf, and phospholipase C-gamma following angiotensin II stimulation, remain to be defined. These tyrosine kinases, activated by angiotensin II, appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Thus, it is important to understand angiotensin II-mediated signaling events, especially those related to tyrosine kinase activity, to develop new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle cells: role of tyrosine kinases. 921 88

Lysophosphatidylcholine (lyso-PC) has been implicated in atherogenesis and the inflammatory process. Although lyso-PC has been reported to contribute to the mitogenic effect of oxidized LDL on rat cultured vascular smooth muscle cells (VSMCs), the signaling mechanisms by which lyso-PC promotes its proliferation are poorly characterized. Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduces extracellular cues to intracellular responses. We therefore examined the effect of lyso-PC on MAP kinase activation, proto-oncogene expression, and AP-1 binding activity using cultured rat VSMC. Marked activation of MAP kinase occurred within 10 minutes of lyso-PC treatment, whereupon rapid inactivation ensued. MAP kinase activation by lyso-PC was concentration-dependent (6.25 to 25 micromol/L). Pertussis toxin treatment did not affect lyso-PC-induced MAP kinase phosphorylation. Lyso-PC (25 micromol/L) also increased the mRNA expression of c-fos and c-jun genes. An electrophoretic mobility shift assay showed that AP-1 binding activity was enhanced by lyso-PC. To examine the upstream signaling of MAP kinase, we used several inhibitors on MAP kinase activation induced by lyso-PC. Although lyso-PC induced sustained increase in intracellular Ca2+ concentration, EGTA had no effect on MAP kinase activation induced by lyso-PC. However, protein kinase C inhibitor GF109203X and downregulation of protein kinase C activity by prolonged treatment with phorbol ester inhibited lyso-PC-induced MAP kinase activation. These data suggest that lyso-PC transmits its mitogenic activity through a MAP kinase-AP-1 pathway, which exists downstream of its protein kinase C activation in VSMCs.
Hypertension 1998 Jan
PMID:Lysophosphatidylcholine stimulates MAP kinase activity in rat vascular smooth muscle cells. 945 11

In this review, the signal events regulated by angiotensin II (AngII) in vascular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis of hypertension, inflammation, atherosclerosis, and congestive heart failure. The expanding role of AngII indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the AngII type I receptor (AT1R) is physiologically most important since pharmacologic inhibitors of the AT1R block most AngII signal events and have beneficial effects on cardiovascular disease. The AT1R is a seven transmembrane-spanning G protein-coupled receptor that regulates intracellular signal events by activation of Gq and Gi. However, many recent data indicate that activation of tyrosine kinases by several different mechanisms contributes to AngII effects in target tissues. Tyrosine kinases activated by AngII include c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 and TYK2), and the receptor tyrosine kinases Ax1, epidermal growth factor, and platelet-derived growth factor. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-gamma after AngII stimulation. These AngII-regulated tyrosine kinases seem to be required for AngII effects such as vasoconstriction, proto-oncogene expression, and protein synthesis based on studies with tyrosine kinase inhibitors. Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. 989 42

We have previously demonstrated that elevating intraluminal pressure from 90 to 140 mm Hg in isolated mesenteric arteries increases the expression of proto-oncogenes. These proto-oncogenes encode nuclear transcription factors that regulate the expression of target genes during various stages of the cell cycle. Thus, pressure-induced proto-oncogene expression may represent a mechanism by which pressure can induce growth and/or proliferation of vascular smooth muscle. The purpose of this study was to determine the intracellular signals that contribute to the pressure-induced increase in c-fos expression. Small mesenteric arteries were isolated from male Wistar rats and transferred to a dual-vessel chamber. The arteries were cannulated and slowly equilibrated to initial conditions (90 mm Hg, 37 degrees C) while being continuously superfused with a HEPES-bicarbonate-buffered Krebs' solution. After the equilibration period, the intraluminal pressure in 1 artery was increased to 140 mm Hg for 1 hour. In experiments designed to determine the intracellular signals involved in the pressure-induced increase in c-fos expression, specific inhibitors were introduced to the superfusate reservoir of both arteries before the pressure increase. The arteries were then fixed in phosphate-buffered formalin and embedded in paraffin blocks. Sections of paraffin-embedded arteries were fixed on slides, and the expression of c-fos was determined by in situ hybridization with the use of (35)S-labeled riboprobes. The pressure-induced expression of c-fos was not inhibited by nitrendipine (10 micromol/L), a calcium-free Krebs' solution containing EGTA (1 to 2 mmol/L), calphostin C (0.1 micromol/L), or cytochalasin D (0.4 micromol/L) but was inhibited by genistein (30 micromol/L). The results suggest that activation of a tyrosine kinase is required for pressure-induced c-fos expression, but the signaling pathway does not require extracellular calcium entry, intact actin filaments, or protein kinase C. As we have shown previously, the expression of c-fos correlated with wall stress.
Hypertension 1999 Jul
PMID:Genistein inhibits pressure-induced expression of c-fos in isolated mesenteric arteries. 1040 36

Angiotensin II modulates beat-to-beat cardiac performance as a potent vasocontrictor, inotrope, and regulator of water and electrolyte balance. It is also a growth factor that can stimulate the early molecular growth responses of proto-oncogene activation and new protein synthesis, and the later event of cardiocyte hypertrophy independent from load. Its effects are mediated through the angiotensin II type 1 (AT1) receptor, which exists as the AT1a and AT1b isoforms, and the angiotensin II type 2 (AT2) receptor. There is still controversy regarding the role of activation of the AT1 receptor subtype(s) as a mandatory signal versus modulatory regulator of the transduction of mechanical load in pressure-overload hypertrophy due to hypertension or aortic stenosis. The role of the AT2 receptor subtype in the heart is even less well understood, although this receptor appears to serve as an antigrowth signal in proliferating cells. Here we review current data on these controversies, including new data that support the notion that angiotensin II activation of the cardiac AT2 receptor subtype inhibits the effects of angiotensin II on the immediate growth response in the adult heart.
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PMID:Role of angiotensin AT1, and AT2 receptors in cardiac hypertrophy and disease. 1075 May 87

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
Hypertension 2000 Sep
PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

The role of c-Src in growth signaling by angiotensin (Ang) II was investigated in vascular smooth muscle cells (VSMCs) from arteries of hypertensive patients. c-Src and extracellular signal-regulated kinase 1/2 (ERK1/2) activity, proto-oncogene expression, activating protein-1 (AP-1) DNA-binding activity, and DNA and protein synthesis were studied in Ang II-stimulated VSMCs derived from small peripheral resistance arteries of normotensive subjects (NTs, n=5) and age-matched untreated hypertensive patients (HTs, n=10). Ang II type 1 (AT(1)) and type 2 (AT(2)) receptor status was also assessed. Ang II dose-dependently increased the synthesis of DNA and protein, with enhanced effects in VSMCs from HTs. PD 098,059, a selective inhibitor of the ERK1/2 pathway, attenuated Ang II-stimulated growth in HTs. The effects of PD 098,059 were greater in HTs than in NTs. In NTs, Ang II transiently increased ERK1/2 phosphorylation, whereas in HTs, Ang II-stimulated actions were augmented and sustained. PP2, a selective Src inhibitor, reduced ERK1/2 activity and normalized ERK1/2 responses in HTs. Ang II-induced c-Src phosphorylation was 2- to 3-fold greater in HTs than in NTs. In HTs but not NTs, kinase activation was followed by overexpression of c-fos and enhanced AP-1 DNA-binding activity. PD 098,059 and PP2 attenuated these responses. AT(1) receptor expression was similar in NTs and HTs. In HT cells transfected with c-fos antisense oligodeoxynucleotide, Ang II-stimulated growth was reduced compared with sense oligodeoxynucleotide. Our findings suggest that augmented Ang II-stimulated VSMC growth is mediated via hyperactivation of c-Src-regulated ERK1/2-dependent pathways, leading to overexpression of c-fos mRNA and enhanced AP-1 DNA-binding activity. Because AT(1) receptor expression was unaltered in HTs, increased Ang II signaling may be a postreceptor phenomenon. These data define a signal transduction pathway whereby Ang II mediates exaggerated growth in VSMCs from HTs.
Hypertension 2001 Jul
PMID:Src is an important mediator of extracellular signal-regulated kinase 1/2-dependent growth signaling by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients. 1146 60


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