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)

We recently reported that norepinephrine and angiotensin II activate the Ras/mitogen-activated protein (MAP) kinase pathway through generation of a cytochrome P450 (CYP450) and lipoxygenase metabolites. The purpose of this study was to determine the contribution of Ras/MAP kinase to deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Administration of DOCA and 1% saline drinking water to uninephrectomized rats for 6 weeks significantly elevated mean arterial blood pressure (MABP) (166+/-5 mm Hg, n=19) compared with that of normotensive controls (95+/-5 mm Hg, n=7) (P<0.05). The activity of Ras and MAP kinase measured in the heart was increased in DOCA-salt hypertensive rats. Infusion of the Ras farnesyl transferase inhibitors FPT III (138 ng/min) and BMS-191563 (694 ng/min) significantly (P<0.05) attenuated MABP to 139+/-4 mm Hg (n=14) and 126+/-1 mm Hg (n=4), respectively. Moreover, infusion of MAP kinase kinase inhibitor PD-98059 (694 ng/min) also reduced MABP in hypertensive rats. Morphological studies of the kidney showed that treatment of rats with FPT III, which reduced Ras activity, minimized the hyperplastic occlusive arteriosclerosis and fibrinoid vasculitis observed in untreated hypertensive rats. In addition, the rise in CYP450 activity and MABP in hypertensive rats was prevented by the CYP450 inhibitor aminobenzotriazole (50 mg/kg) and was associated with a decrease in Ras and MAP kinase activity in the heart. These data suggest that the Ras/MAP kinase pathway contributes to DOCA-salt-induced hypertension and associated vascular pathology consequent to activation of CYP450.
Hypertension 2000 Jan
PMID:Contribution of Ras GTPase/MAP kinase and cytochrome P450 metabolites to deoxycorticosterone-salt-induced hypertension. 1064 41

We reported that norepinephrine and angiotensin II (Ang II) activate the Ras/mitogen-activated protein (MAP) kinase pathway primarily through the generation of cytochrome P450 (CYP450) metabolites. The purpose of the present study was to determine the contribution of Ras and CYP450 to Ang II-dependent hypertension in rats. Infusion of Ang II (350 ng/min for 6 days) elevated mean arterial blood pressure (MABP) (171+/-3 mm Hg for Ang II versus 94+/-5 for vehicle group, P<0.05). Ras is activated on farnesylation by farnesyl protein transferase (FPT). When Ang II was infused in combination with FPT inhibitor FPT III (232 ng/min) or BMS-191563 (578 ng/min), the development of hypertension was attenuated (171+/-3 mm Hg for Ang II plus vehicle versus 134+/-5 mm Hg for Ang II plus FPT III and 116+/-6 mm Hg for Ang II plus BMS-191563, P<0.05). Treatment with the MAP kinase kinase inhibitor PD-98059 (5 mg SC) reduced MABP. The CYP450 inhibitor aminobenzotriazole (50 mg/kg) also diminished the development of Ang II-induced hypertension to 113+/-8 mm Hg. The activities of Ras, MAP kinase, and CYP450 measured in the kidney were elevated in hypertensive animals. The infusion of FPT III, BMS-191563, or aminobenzotriazole reduced the elevation in Ras and MAP kinase activity. Morphological studies of the kidney showed that FPT III treatment ameliorated the arterial injury, vascular lesions, fibrinoid necrosis, focal hemorrhage, and hypertrophy of muscle walls observed in hypertensive animals. These data suggest that the activation of Ras and CYP450 contributes to the development of Ang II-dependent hypertension and associated vascular pathology.
Hypertension 2000 Oct
PMID:Angiotensin II-induced hypertension: contribution of Ras GTPase/Mitogen-activated protein kinase and cytochrome P450 metabolites. 1104 Feb 43

Recent evidence suggests the possible involvement of inducible nitric oxide synthase (iNOS) in the development and maintenance of hypertension in certain animal models. Inflammatory cytokines activate nuclear factor (NF)-kappaB, which plays a major role in transactivation of the inducible nitric oxide synthase (iNOS) gene. However, it remains unknown whether cytokine-mediated iNOS expression in vascular smooth muscle cells (VSMCs) requires signaling pathway(s) other than NF-kappaB activation. The purpose of this study was to determine whether the p42/p44 MAP kinase pathway is involved in cytokine-induced NF-kappaB activation and/or iNOS expression in cultured rat VSMCs. Nitrite/nitrate (NOx) production stimulated by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha in VSMCs was markedly suppressed by inhibiting MAP kinase by pretreatment with a p42/p44 MAP kinase kinase (MAPKK)-1 inhibitor (PD98059) or by transfecting the dominant-interfering form of the nonphosphorylated MAPKK-1 expressing construct (MAPKK S222A). Inhibition of p42/p44 MAP kinase also antagonized the upregulation of iNOS mRNA and protein, as demonstrated by the quantitative RT-PCR method and Western blot analysis, respectively. Furthermore, rat iNOS promoter activity using an iNOS-luciferase construct stimulated by cytokines was inhibited by MAPKK-1 inhibition. However, kappaB-dependent transcription analysis revealed that cytokine-stimulated NF-kappaB activity was unaffected by MAP kinase inhibition. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies showed that PD98059 had no effect on transient phosphorylation or degradation of IkappaB-alpha by cytokines. An electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that MAP kinase inhibition did not block cytokine-stimulated activation of NF-kappaB. These data suggest that the MAP kinase pathway is in part involved in cytokine-induced iNOS expression independent from NF-kappaB activation in rat VSMCs.
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PMID:Cytokine-activated p42/p44 MAP kinase is involved in inducible nitric oxide synthase gene expression independent from NF-kappaB activation in vascular smooth muscle cells. 1113 Dec 79

Obese hypertensive patients with cardiovascular risk factor clustering and increased risk for atherosclerotic disease have increased plasma nonesterified fatty acid levels, including oleic acid (OA), and a more active renin-angiotensin-aldosterone system. Vascular smooth muscle cell (VSMC) migration and proliferation participate in the development of atherosclerotic plaque. OA and angiotensin (Ang) II induce synergistic mitogenic responses in VSMCs through sequential signaling pathways dependent on the activation of protein kinase C (PKC), oxidants (reactive oxygen species, ROS), and extracellular signal-regulated kinase (ERK) activation. We tested the hypotheses that (1) OA and Ang II have additive or synergistic effects on VSMC migration and (2) PKC, ROS, and mitogen-activated protein kinase are critical signaling molecules. OA at 100 micromol/L increases VSMC migration 60+/-10% over control (P:<0.001). Ang II (10(-)(9) mol/L) increases VSMC migration by 62+/-13% and 73% over control, respectively (P:<0.01). Coincubation of cells with OA and Ang II produces a nearly additive increase in VSMC cell migration at 107+/-20% (P:<0.01). Increases in VSMC migration induced by OA alone and combined with Ang II were reduced by PKC inhibition and downregulation. VSMC migration in response to OA alone and with Ang II was also inhibited by N:-acetyl-cysteine, MEK inhibition, and ERK antisense. VSMC migration in response to OA alone or combined with Ang II is dependent on activation of PKC, ROS, and ERK activation, further raising the possibility that increased plasma nonesterified fatty acids and an activated renin-angiotensin-aldosterone system in subjects with the risk factor cluster contribute to accelerated atherosclerosis through a PKC, ROS, and ERK-dependent signaling pathway.
Hypertension 2001 Feb
PMID:Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. 1123 Feb 90

Angiotensin II (Ang II) activates cytosolic phospholipase A(2) (cPLA(2)) and phospholipase D (PLD) in rabbit vascular smooth muscle cells (VSMCs). Ang II also activates ras/mitogen-activated protein (MAP) kinase in VSMCs; this activation is mediated by 20-hydroxyeicosatetraenoic acid (HETE) and 12(S)-HETE, which are metabolites of arachidonic acid generated by cytochrome P450 4A and lipoxygenase, respectively, produced on activation of cPLA(2). The purpose of this study was to determine if Ang II-induced PLD activation in VSMCs is mediated through the ras/extracellular signal-regulating kinase (ERK) pathway by arachidonic acid metabolites that are generated consequent to cPLA(2) stimulation. Inhibitors of PLD (C(2) ceramide), phosphatidate phosphohydrolase (propranolol), and diacylglycerol lipase (RHC 80267) attenuated Ang II-induced arachidonic acid release. Ang II-induced PLD activation, as measured by [(3)H]phosphatidylethanol production, was inhibited by C(2) ceramide but not by propranolol or RHC 80267. Ang II-induced PLD activation was decreased by the inhibitor methyl arachidonylfluorophosphate (MAFP) and the antisense oligonucleotide of cPLA(2). Inhibitors of lipoxygenases (baicalein) and cytochrome P450 4A (ODYA) attenuated Ang II-induced PLD activation. 20-HETE and 12(S)-HETE increased PLD activity. Inhibitors of ras farnesyltransferase (FPT III and BMS-191563) and MAP kinase kinase (UO126) attenuated the increase in PLD activity elicited by 20-HETE and Ang II. PLD2 was the main isoform activated by Ang II in VSMCs. These data suggest that the CYP4A metabolite 20-HETE, which is generated from arachidonic acid after cPLA(2) activation by Ang II, stimulates the ras/MAP kinase pathway, which in turn activates PLD2 and releases further arachidonic acid for prostaglandin synthesis through the phosphatidate phosphohydrolase/diacylglycerol lipase pathway.
Hypertension 2001 Feb
PMID:20-Hydroxyeicosatetraenoic acid mediates angiotensin ii-induced phospholipase d activation in vascular smooth muscle cells. 1123 Mar 46

Plasminogen activator inhibitor type-1 (PAI-1) plays an integral role not only in the regulation of fibrinolytic activity but also in the pathogenesis of atherosclerosis and hypertension. We investigated the signaling pathways of angiotensin II (Ang II) leading to PAI-1 gene expression. Ang II increased the PAI-1 mRNA and protein levels in a time- and dose-dependent manner through the Ang II type 1 receptor in vascular smooth muscle cells. PAI-1 gene promoter activity measured by luciferase assay was significantly increased by Ang II. PAI-1 mRNA stability was also increased by Ang II. Ang II-induced PAI-1 mRNA upregulation was inhibited by BAPTA-AM, genistein, and AG1478, suggesting that intracellular calcium, tyrosine kinase, and epidermal growth factor receptor transactivation are involved. Furthermore, PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) kinase (MEK), almost completely suppressed Ang II-induced PAI-1 upregulation. Adenovirus-mediated overexpression of the dominant-negative form of Rho-kinase or Y27632, a Rho-kinase inhibitor, also completely prevented PAI-1 induction by Ang II without affecting Ang II-induced ERK activation. These data suggest that activation of MEK/ERK and Rho-kinase pathways plays a pivotal role in PAI-1 gene upregulation by Ang II. The Rho-kinase pathway may be a novel target to inhibit Ang II signaling, and its inhibition may be useful in the treatment of hypertension as well as atherosclerosis.
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PMID:Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. 1134 89

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.
Hypertension 2002 Jan
PMID:Angiotensin II type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. 1179 93

To understand the signaling mechanisms of atrial natriuretic peptide (ANP) receptor-A (NPRA), we studied the effect of the ANP/NPRA system on mitogen-activated protein kinases (MAPKs), with particular emphasis on the extracellular-regulated kinase (Erk2) and stress-activated protein kinase (p38MAPK) in cultured human vascular smooth muscle cells (HVSMC). Angiotensin II (ANG II) and platelet-derived growth factor (PDGF) stimulated the immunoreactive Erk2 and p38MAPK activities and their protein levels by 2-4 fold. The pretreatment of cells with ANP significantly inhibited the agonist-stimulated Erk2 and p38MAPK activities and protein expression by 65-75% in HVSMC transiently transfected with NPRA, as compared with only 18-22% inhibition in vector-transfected cells. The pretreatment of cells with KT5823, an inhibitor of cGMP-dependent protein kinase (PKG), reversed the inhibitory effects of ANP on MAPK activities and protein expression by 90-95%. PD98059, which inhibits Erk2 by directly inhibiting the MAPK-kinase (MEK), and SB202192, a selective antagonist of p38MAPK, blocked the Erk2 and p38MAPK activities, respectively. Interestingly, ANP stimulated the MAPK-phosphatase-3 (MKP-3) protein levels by more than 3-fold in HVSMC over-expressing NPRA, suggesting that ANP-dependent inhibition of MAPKs may also proceed by stimulating the phosphatase cascade. These present findings provide the evidence that ANP exerts inhibitory effects on agonist-stimulated MAPKs (Erk2 and p38MAPK) activities and protein levels in a 2-fold manner: by antagonizing the up-stream signaling pathways and by activation of MKP-3 to counter-regulate MAPKs in a cGMP and PKG-dependent manner. Our results identify a signal transduction pathway in HVSMC that could contribute to vascular remodeling and structural changes in human hypertension.
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PMID:Expression of atrial natriuretic peptide receptor-A antagonizes the mitogen-activated protein kinases (Erk2 and P38MAPK) in cultured human vascular smooth muscle cells. 1208 72

Although oxidized lipoproteins may play an important role in the progression of atherosclerosis, no report has mentioned the significance of oxidized lipoprotein (a) (Lp[a]) in the pathogenesis of cardiovascular disease. Initially, we compared the mitogenic actions of Lp(a) and oxidized Lp(a) on human vascular smooth muscle cells (VSMC). Lp(a) significantly stimulated the growth of human VSMC in a dose-dependent manner, whereas oxidized Lp(a) showed a stronger stimulatory action on VSMC growth than native Lp(a). Interestingly, antioxidants probucol and fluvastatin inhibited the oxidation of Lp(a). Moreover, the stimulatory effect of oxidized Lp(a) on human VSMC growth was significantly inhibited by probucol. Finally, we elucidated the molecular mechanisms of how Lp(a) stimulated the growth of VSMC. Extracellular signal-regulated kinase (ERK), as those controlled by kinases, modulate critical cellular functions such as cell growth, differentiation, and apoptosis, was transiently phosphorylated by oxidized Lp(a) as well as native Lp(a) from 5 minutes, and the phosphorylation disappeared within 30 minutes. The degree of ERK phosphorylation by oxidized Lp(a) was much higher than that by native Lp(a). Administration of a specific inhibitor of MEK, PD 98059, significantly attenuated VSMC growth induced by native Lp(a) or oxidized Lp(a) in a dose-dependent manner (P<0.01). The current study demonstrated that oxidized Lp(a) is more potent than native Lp(a) in stimulating VSMC growth. Oxidized Lp(a) may play an important role in the pathogenesis of vascular disease.
Hypertension 2002 Sep
PMID:Mitogenic activity of oxidized lipoprotein (a) on human vascular smooth muscle cells. 1221 72

Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor beta-receptor (PDGF-beta-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 micromol/L) or PDGF-BB (30 microg/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT1) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT2 antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-beta-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-beta-R was supported by experiments with unmounted vessels in which PDGF-beta-R activation was measured by Western blot; both PDGF-BB and Ang II-mediated PDGF-beta-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-beta-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-beta-R.
Hypertension 2003 Apr
PMID:Pressure-induced activation of extracellular signal-regulated kinase 1/2 in small arteries. 1262 63


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