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)

Migration of vascular smooth muscle cells (VSMCs) is a crucial response to vascular injury resulting in neointima formation and atherosclerosis. Platelet-derived growth factor (PDGF-BB) functions as a potent chemoattractant for VSMCs and enhances these pathologies in the vasculature. However, little is known about the intracellular pathways that mediate VSMC migration. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK) activation in this function, since PDGF-BB as well as other growth factors activate this pathway. Using an in-gel kinase assay, we observed that PD 98059 an inhibitor of MEK that activates MAP kinase, inhibited PDGF-BB-induced activation of ERK-1 and ERK-2 in cultured rat aortic smooth muscle cells in a concentration-dependent manner. In contrast, PDGF-mediated activation of intracellular calcium release was not affected by PD 98059. The chemotactic response of both rat aortic smooth muscle cells (RASMCs) and human umbilical vein smooth muscle cells (HUSMCs) toward PDGF-BB (10 ng/mL) was significantly reduced by PD 98059 (10 mumol/L) to 41.7 +/- 7.1% in RASMCs (P < .01) and to 47.2 +/- 5.3% in HUSMCs (P < .01). Similar inhibition was seen at 30 mumol/L, less at 1 mumol/L. To further confirm the specificity of these results implicating the MAPK pathway, an antisense oligodeoxynucleotide (ODN) directed against the initiation translation site of rat ERK-1 and ERK-2 mRNA was used to suppress MAP kinase synthesis and function in rat VSMCs. Liposomal transfection with 0.4 mumol/L antisense ODN reduced ERK-1 and ERK-2 protein by 65% (P < .01) after 48 hours. The chemotactic response to PDGF-BB (10 ng/mL) was reduced by 75% (P < .01) in rat VSMCs transfected with the same antisense ODN concentration. Sense and scrambled control ODNs (0.4 mumol/L) did not affect ERK-1 and ERK-2 protein concentrations or chemotaxis of VSMCs induced by PDGF-BB. These experiments provide the first evidence that activation of MAPK is a critical event in PDGF-mediated signal transduction regulating VSMC migration.
Hypertension 1997 Jan
PMID:Mitogen-activated protein kinase activation is involved in platelet-derived growth factor-directed migration by vascular smooth muscle cells. 903 24

The neuronal angiotensin II (Ang II) type 1 (AT1) receptor is coupled to the Ras-Raf-1-mitogen-activated protein (MAP) kinase signal-transduction pathway (Yang H, Lu D, Yu K, Raizada MK. Regulation of neuromodulatory actions of angiotensin II in the brain neurons by the Ras-dependent mitogen-activated protein kinase pathway. J Neurosci. 1996;16:4047-4058). In this study we compared the effects of angiotensin II (Ang II) on AT1 receptor phosphorylation and the ability of the phosphorylated receptor to bind Ang II in neuronal cultures of Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR) brains to further our understanding of the Ang II signaling mechanism. Ang II caused a time-dependent phosphorylation of AT1 receptors in both WKY and SHR brain neurons. The level of phosphorylation was higher in the SHR brain neurons; this finding was consistent with increased AT1 receptors in these cells. MAP kinase was involved in this phosphorylation, a conclusion supported by the following evidence: (1) exogenous MAP kinase phosphorylated the AT1 receptor; (2) PD98059, a MAP kinase kinase inhibitor, attenuated Ang II-stimulated AT1 receptor phosphorylation; and (3) MAP kinase and AT1 receptors were coimmunoprecipitated in Ang II-stimulated neurons. Finally, MAP kinase phosphorylation was associated with the loss of 125I-[Sar1-Ile8]-Ang II binding ability of the AT1 receptor in both strains of neurons. These observations show that Ang II stimulates phosphorylation of the neuronal AT1 receptor by a mechanism involving MAP kinase and that the phosphorylated neuronal AT1 receptor does not exhibit Ang II binding activity in the brains of either WKY or SHR.
Hypertension 1997 Sep
PMID:Angiotensin II-induced phosphorylation of the AT1 receptor from rat brain neurons. 931 16

Norepinephrine (NE) stimulates release of arachidonic acid (AA) from tissue lipids in blood vessels, which is metabolized via cyclooxygenase, lipoxygenase (LO), and cytochrome P-450 (CYP-450) pathways to biologically active products. Moreover, NE and AA have been shown to stimulate proliferation of vascular smooth muscle cells (VSMCs) of rat aorta. The purpose of this study was to determine the possible contribution of AA and its metabolites to NE-induced mitogenesis in VSMCs of rat aorta and the underlying mechanism of their actions. NE (0.1 to 10 micromol/L) increased DNA synthesis as measured by [3H]thymidine incorporation in VSMCs, and this effect was attenuated by inhibitors of CYP-450 (17-octadecynoic acid, 5 micromol/L; 12-diabromododec-11-enoic acid, 10 micromol/L; and dibromo-dodecenyl-methylsulfimide, 10 micromol/L) and by the LO inhibitor (baicalein, 20 micromol/L), but not by the cyclooxygenase inhibitor (indomethacin, 5 micromol/L). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) (0.1 to 0.5 micromol/L) and 12(S)-HETE, respectively, increased [3H]thymidine incorporation in VSMCs. Both NE and 20-HETE increased mitogen activated protein (MAP) kinase activity as measured by the in-gel kinase assay. The inhibitor of MAP kinase kinase, PD-98059 (50 micromol/L), attenuated NE as well as 20-HETE induced [3H]thymidine incorporation and MAP kinase activation in VSMCs. These data suggest that products of AA formed via CYP-450, most likely 20-HETE, and via LO mediate NE induced mitogenesis in VSMCs.
Hypertension 1998 Jan
PMID:Cytochrome P-450 metabolites mediate norepinephrine-induced mitogenic signaling. 945 10

The activation of mitogen-activated protein (MAP) kinase and increase in intracellular free calcium concentration ([Ca2+]i) are discussed in reference to activation of different protein kinases and growth of vascular smooth muscle cells (VSMCs). The aim of the present study was to investigate the role of angiotensin (Ang) II-induced increase in [Ca2+]i for activation of 44-kD/42-kD MAP kinase (p44mapk/p42mapk) and DNA synthesis in VSMCs. Experiments were performed by chelation of [Ca2+]i by the intracellular chelator 1,2-bis-(o-amino-5-methylphenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (MAPTAM). Ca2+ was measured by the fura 2 method. MAP kinase activation was determined by the Western blotting method. DNA synthesis was determined by measurement of [3H]thymidine incorporation into the cell DNA. Treatment of VSMCs with 20 micromol/L MAPTAM for 30 minutes resulted in a complete abolishment of the maximal Ang II-induced increase at 10 seconds. Ang II phosphorylated the p44mapk/p42mapk in a time-dependent manner, showing a maximum at 3 minutes. In MAPTAM-treated cells, the maximal phosphorylation of MAP kinase isoforms was shifted to 5 minutes, and dephosphorylation was delayed compared with untreated cells. In concordance with this finding, the induction of the MAP kinase phosphatase-1 was markedly impaired in MAPTAM-treated cells. Ang II induced a 2.3-fold increase in [3H]thymidine incorporation into DNA synthesis in untreated cells. This effect was not reduced in MAPTAM-treated cells. Treatment of the cells with PD 98059 (10 micromol/L), a MAP kinase kinase inhibitor, caused 85% inhibition of the Ang II-induced activation of MAP kinases but did not inhibit the Ang II-induced DNA synthesis. In conclusion, the Ang II-induced stimulation of the MAP kinase is a Ca2+-dependent process. Furthermore, blockade of the Ang II-induced stimulation of the early intracellular events, such as increase in [Ca2+]i or phosphorylation of the MAP kinase, is not accompanied by an inhibition of the Ang II-induced DNA synthesis.
Hypertension 1998 May
PMID:Role of mitogen-activated protein kinase in the angiotensin II-induced DNA synthesis in vascular smooth muscle cells. 957 28

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Hyperinsulinemia (HI) and insulin resistance (IR) are frequently associated with hypertension and atherosclerosis. However, the exact roles of HI and IR in the development of hypertension are unclear. Mitogen-activated protein kinases (MAPK) are well-characterized intracellular mediators of cell proliferation. In this study, we examined the contribution of MAPK pathway in insulin-stimulated mitogenesis using primary vascular smooth muscle cells (VSMCs) isolated from aortas of normotensive Wistar-Kyoto rats (WKY) and spontaneous hypertensive rats (SHR). VSMCs were grown to confluence in culture, serum starved, and examined for DNA synthesis (using [3H]thymidine (TDR), immunoprecipitated MAPK activity, and MAPK phosphatase (MKP-1) induction). Basal rate of TDR incorporation into DNA was twofold higher in SHR compared with WKY (P < 0.005). Insulin caused a dose-dependent increase in TDR incorporation (150% over basal levels with 100 nM in 12 h). Stimulation was sustained for 24 h with a decline toward basal in 36 h. Pretreatment with insulin-like growth factor I (IGF-I) receptor antibody did not abolish mitogenesis mediated by 10-100 nM insulin, suggesting that insulin effect is mediated via its own receptors. Insulin had a small mitogenic effect in WKY (33% over basal). Insulin-stimulated mitogenesis was accompanied by a dose-dependent increase in MAPK activity in SHR, with a peak activation (>2-fold over basal) between 5 and 10 min with 100 nM insulin. Insulin had very small effects on MAPK activity in WKY. In contrast, serum-stimulated MAPK activation was comparable in WKY and SHR. Pretreatment with MEK inhibitor, PD-98059, completely blocked insulin's effect on MAPK activation and mitogenesis. Inhibition of phosphatidylinositol 3-kinase with wortmannin also prevented insulin's effects on MAPK activation and mitogenesis. In WKY, insulin and IGF-I treatment resulted in a rapid induction of MKP-1, the dual-specificity MAPK phosphatase. In contrast, VSMCs from SHR were resistant to insulin with respect to MPK-1 expression. We conclude that insulin is mitogenic in SHR, and the effect appears to be mediated by sustained MAPK activation due to impaired insulin-mediated MKP-1 mRNA expression, which may act as an inhibitory feedback loop in attenuating MAPK signaling.
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PMID:Vascular smooth muscle cell growth and insulin regulation of mitogen-activated protein kinase in hypertension. 968 33

Angiotensin II (Ang II), via its interaction with the angiotensin type 1 (AT1) receptor subtype, causes enhanced stimulation of norepinephrine (NE) neuromodulation. This involves increased transcription of NE transporter, tyrosine hydroxylase, and dopamine ss-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons. AT1 receptor-mediated regulation of certain signaling events (such as activation of the Ras-Raf-1-mitogen activated protein (MAP) kinase signaling pathway, nuclear translocation of transcription factors such as Fos and Jun, and the interactions of these factors with AP-1 binding sites) is involved in this NE neuromodulation (Lu et al. J Cell Biol. 1996;135:1609-1617). The aim of this study was to compare the signal transduction mechanism of Ang II regulation of NE neuromodulation in WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of the fact that AT1 receptor expression and Ang II stimulation of NE neuromodulation are higher in SHR neurons compared with WKY neurons. Despite this hyperactivity, Ang II stimulation of Ras, Raf-1, and MAP kinase activities was comparable between the neurons from WKY and SHR. Similarly, central injections of Ang II caused a comparable stimulation of MAP kinase in the hypothalamic and brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by either an MAP kinase kinase inhibitor (PD98059) or an MAP kinase antisense oligonucleotide completely attenuated the stimulatory effects of Ang II on [3H]-NE uptake, NE transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons. These treatments resulted in only 43% to 50% inhibition of [3H]-NE uptake and NE transporter and tyrosine hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE neuromodulation was completely blocked by MAP kinase inhibition in WKY neurons and only partially blocked in the SHR neurons. These observations suggest the presence of an additional signal transduction pathway involved in NE neuromodulation in SHR neurons that is independent of the MAP kinase pathway.
Hypertension 1998 Sep
PMID:MAP kinase-independent signaling in angiotensin II regulation of neuromodulation in SHR neurons. 974 Jun 13

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

Angiotensin II and hypertension increase vascular oxidant stress. We examined how these might affect expression of the extracellular superoxide dismutase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis. This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1. d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase; however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderately increased transcriptional rate (as assessed by nuclear run-on analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative state of the vessel wall in pathological processes in which the renin-angiotensin system is activated.
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PMID:Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. 1040 Sep 7

Angiotensin (Ang) II stimulates proliferation of vascular smooth muscle cells (VSMC) via its specific receptor AT1 subtype, possibly leading to atherosclerosis in hypertension. On the other hand, a cytokine interferon (IFN)-gamma has been shown to have an anti-atherosclerotic effect. In the present study, we examined a possible role of IFN-gamma in AT1 receptor gene regulation in VSMC. A firefly luciferase expression vector driven by the rat AT1a receptor gene promoter ( approximately 3.2 kb) was transfected into the cultured rat VSMC, and luciferase expression was determined to estimate the transcription function of the AT1a receptor gene promoter. RT-PCR was also carried out to determine mRNA expression of AT1a receptor in VSMC. IFN-gamma treatment decreased AT1a receptor mRNA expression as well as luciferase expression in a dose-dependent manner. The analysis with deletion DNA fragments showed that the IFN-responsive element was located between -987 and -331 positions, where multiple GAS (gamma interferon activated site)-like elements were identified. The expression suppression was reversed by either a MAPKK inhibitor PD98059 or a Jak-2 inhibitor AG-490. These results suggest that IFN-gamma can inhibit AT1 receptor expression at gene transcription level, and that the transcription suppression is dependent on MAP kinase and Jak-2. Inhibition of AT1a receptor expression may possibly be implicated in the anti-atherosclerotic action of IFN-gamma in VSMC.
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PMID:Transcriptional suppression of rat angiotensin AT1a receptor gene expression by interferon-gamma in vascular smooth muscle cells. 1046 2


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