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 in vivo signal transduction pathway, responsible for hypertension-induced glomerular injury, remains to be clarified. In this study, the effect of angiotensin II (Ang II)-induced hypertension was examined on glomerular mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), and on glomerular transcription factors activator protein-1 (AP-1) and Sp 1. MAPK activities were determined by in-gel kinase assay. DNA binding activity of AP-1 and Sp 1 was determined by gel mobility shift assay. Continuous infusion of Ang II (1000 ng/kg per min, intravenously) to conscious rats rapidly increased BP, followed by the rapid and transient activation of glomerular p42 and p44 ERK and p46 and p55 JNK with the peak at 15 to 180 min. Glomerular AP-1 binding activity was increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II infusion. Supershift analysis showed that the activated AP-1 complexes contained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 DNA binding activity was not changed throughout 7 d of Ang II infusion. These results provided the first in vivo evidence that Ang II-induced hypertension causes the activation of glomerular ERK and JNK, leading to the activation of AP-1. Thus, ERK and JNK signaling cascades, via the activation of AP-1, may be implicated in the development of hypertension-induced glomerular injury.
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PMID:Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension. 951 99

Nonesterified fatty acids (NEFAs) are acutely liberated during lipolysis and are chronically elevated in pathological conditions, such as insulin resistance, hypertension, and obesity, which are known risk factors for atherosclerosis. The purpose of this study was to investigate the effect and mechanism of action of NEFAs on the epithelial growth factor (EGF) receptor (EGFR). In the ECV-304 endothelial cell line, unsaturated fatty acids triggered a time- and dose-dependent tyrosine phosphorylation of EGFR (polyunsaturated fatty acids [PUFAs] were the most active), whereas saturated FAs were inactive. Although less potent than PUFAs, oleic acid (OA) was used because it is prominent in the South European diet and is only slightly oxidizable (thus excluding oxidation derivatives). EGFR is activated by OA independent of any autocrine secretion of EGF or other related mediators. OA-induced EGFR autophosphorylation triggered EGFR signaling pathway activation (as assessed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and SHP-2) and subsequent p42/p44 mitogen-activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK(+) cell lines). OA induced in vitro both autophosphorylation and activation of intrinsic tyrosine kinase of immunopurified EGFR, thus suggesting that EGFR is a primary target of OA. EGFR was also activated by mild surfactants, Tween-20 and Triton X-100, both in vitro (on immunopurified EGFR) and in intact living cells, thus indicating that EGFR is sensitive to amphiphilic molecules. These data suggest that EGFR is activated by OA and PUFAs, acts as a sensor for unsaturated fatty acids (and amphiphilic molecules), and is a potential transducer by which diet composition may influence vascular wall biology.
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PMID:Activation of epithelial growth factor receptor pathway by unsaturated fatty acids. 1055 35

We previously showed that arginine vasopressin (AVP) stimulates heat shock protein 27 (HSP27) induction through protein kinase C activation in aortic smooth muscle A10 cells. In the present study, we examined whether the mitogen-activated protein (MAP) kinase superfamily is involved in the AVP-stimulated HSP27 induction in A10 cells. AVP stimulated the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase. On the contrary, AVP had little effect on SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase) phosphorylation. The HSP27 accumulation by AVP was not affected by PD98059, an inhibitor of the upstream kinase that activates p42/p44 MAP kinase. SB203580 and PD169316, specific inhibitors of p38 MAP kinase, suppressed the AVP-induced accumulation of HSP27. 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C, induced accumulation of HSP27 and was not inhibited by PD98059 but was inhibited by SB203580. Calphostin C and ET-18-OCH(3), inhibitors of protein kinase C, reduced the phosphorylation of p38 MAP kinase by AVP. SB203580 and PD169316 suppressed the AVP-increased levels in mRNA for HSP27. Dissociation of the aggregated HSP27 to the dissociated HSP27 was induced by AVP. These results strongly suggest that p38 MAP kinase takes part in the pathway of the AVP-stimulated induction of HSP27 in vascular smooth muscle cells.
Hypertension 2000 Feb
PMID:p38 MAP kinase is required for vasopressin-stimulated HSP27 induction in aortic smooth muscle cells. 1067 16

We have reported previously that N-acetyl-L-cysteine facilitated interleukin-1beta-induced nitric oxide synthase (iNOS) expression in rat vascular smooth muscle cells. The present study compares the effect of N-acetyl-L-cysteine with other antioxidants and tested the possibility that N-acetyl-L-cysteine potentiates iNOS induction by a mechanism involving activation of p44/42 mitogen-activated protein kinases (MAPKs). The effect of N-acetyl-L-cysteine on potentiating interleukin-1beta-induced nitrite production and iNOS expression was mimicked either by the enantiomers, L-cysteine and D-cysteine, or by a non-thiol-containing antioxidant, L-ascorbic acid. Interleukin-1beta activated p44/42 MAPK, and this activation was enhanced in the presence of N-acetyl-L-cysteine. Inhibition of p44/42 MAPK phosphorylation by the selective inhibitor PD98059 clearly inhibited iNOS expression induced by interleukin-1beta either in the absence or in the presence of N-acetyl-L-cysteine. These observations, combined with previous results, indicate that p44/42 MAPK activation is required for interleukin-1beta induction of iNOS and that N-acetyl-L-cysteine may act as a reducing agent and facilitate interleukin-1beta-induced iNOS expression through a reduction/oxidation-related mechanism involving potentiation of cytokine activation of the p44/42 MAPK signaling pathway.
Hypertension 2000 Apr
PMID:N-Acetyl-L-cysteine potentiates interleukin-1beta induction of nitric oxide synthase : role of p44/42 mitogen-activated protein kinases. 1077 61

Bradykinin stimulates proliferation of aortic vascular smooth muscle cells (VSMCs). We investigated the action of bradykinin on the phosphorylation state of the mitogen-activated protein kinases p42(mapk) and p44(mapk) in VSMCs and tested the hypothesis that reactive oxygen species (ROS) might be involved in the signal transduction pathway linking bradykinin activation of nuclear transcription factors to the phosphorylation of p42(mapk) and p44(mapk). Bradykinin (10(-8) mol/L) rapidly increased (4- to 5-fold) the phosphorylation of p42(mapk) and p44(mapk) in VSMCs. Preincubation of VSMCs with either N-acetyl-L-cysteine and/or alpha-lipoic acid significantly decreased bradykinin-induced cytosolic and nuclear phosphorylation of p42(mapk) and p44(mapk). In addition, the induction c-fos mRNA levels by bradykinin was completely abolished by N-acetyl-L-cysteine and alpha-lipoic acid. Using the cell-permeable fluorescent dye dichlorofluorescein diacetate, we determined that bradykinin (10(-8) mol/L) rapidly increased the generation of ROS in VSMCs. The NADPH oxidase inhibitor diphenylene iodonium (DPI) blocked bradykinin-induced c-fos mRNA expression and p42(mapk) and p44(mapk) activation, implicating NADPH oxidase as the source for the generation of ROS. These findings demonstrate that the phosphorylation of cytosolic and nuclear p42(mapk) and p44(mapk) and the expression of c-fos mRNA in VSMCs in response to bradykinin are mediated via the generation of ROS and implicate ROS as important mediators in the signal transduction pathway through which bradykinin promotes VSMC proliferation in states of vascular injury.
Hypertension 2000 Apr
PMID:Role of reactive oxygen species in bradykinin-induced mitogen-activated protein kinase and c-fos induction in vascular cells. 1077 66

Previously, we and others have shown that angiotensin II enhances vascular smooth muscle cell extracellular matrix synthesis via stimulation of the angiotensin II type 1 (AT(1)) receptor. Recently, expression of the type 2 (AT(2)) receptor has been confirmed in the adult vasculature, but its role has not yet been fully defined. The aim of the present study was to examine the effects of stimulation of AT(2) receptors on collagen synthesis in vascular smooth muscle cells. Retroviral gene transfer was used to supplement adult vascular smooth muscle cells with AT(2) receptors to mimic the vasculature in vivo. The treatment of these cells with the AT(2) receptor agonist CGP42212A (10(-7) mol/L) alone did not cause a significant change in p42/p44 MAP kinase activity but caused a modest (30% to 50%) decrease in protein tyrosine phosphatase activity. Treatment with CGP42112A also caused a dose- and time-dependent increase in both cell-associated and secretory collagen synthesis (148+/-17% of control at 48 hours, P<0.05), which was completely inhibited by the AT(2) receptor antagonist PD123319, unaffected by the AT(1) receptor antagonist losartan, and attenuated by treatment with pertussis toxin or G(alpha)(i) antisense oligonucleotides. Interestingly, studies in other cell lines demonstrated that CGP42112A caused similar results in transfected mesangial cells but had essentially opposite effects in fibroblasts (NIH-3T3-AT(2)). These results suggest that AT(2) receptor stimulation can increase collagen synthesis in vascular smooth muscle cells via a G(alpha)(i)-mediated mechanism and provide evidence for heterogeneity in the effects of AT(2) receptor stimulation in different tissues.
Hypertension 2000 Nov
PMID:Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells. 1108 54

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

N:-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell entry into the S phase of the cell cycle and is normally present in human plasma. Ac-SDKP is exclusively hydrolyzed by ACE, and its plasma concentration is increased 5-fold after ACE inhibition in humans. We examined the effect of 0.05 to 100 nmol/L Ac-SDKP on 24-hour (3)H-thymidine incorporation (DNA synthesis) by cardiac fibroblasts both in the absence and presence of 5% FCS. Captopril (1 micromol/L) was added in all cases to prevent the degradation of Ac-SDKP. Treatment of cardiac fibroblasts with 5% FCS increased thymidine incorporation from a control value of 12 469+/-594 to 24 598+/-1051 cpm (P:<0.001). Cotreatment with 1 nmol/L Ac-SDKP reduced stimulation to control levels (10 373+/-200 cpm, P:<0.001). We measured hydroxyproline content and incorporation of (3)H-proline into collagenous fibroblast proteins and found that Ac-SDKP blocked endothelin-1 (10(-8) mol/L)-induced collagen synthesis in a biphasic and dose-dependent manner, causing inhibition at low doses, whereas high doses had little or no effect. It also blunted the activity of p44/p42 mitogen-activated protein kinase in a biphasic and dose-dependent manner in serum-stimulated fibroblasts, suggesting that the inhibitory effect of DNA and collagen synthesis may depend in part on blocking mitogen-activated protein kinase activity. Participation of p44/p42 in collagen synthesis was confirmed, because a specific inhibitor for p44/p42 activation (PD 98059, 25 micromol/L) was able to block endothelin-1-induced collagen synthesis, similar to the effect of Ac-SDKP. The fact that Ac-SDKP inhibits DNA and collagen synthesis in cardiac fibroblasts suggests that it may be an important endogenous regulator of fibroblast proliferation and collagen synthesis in the heart. Ac-SDKP may participate in the cardioprotective effect of ACE inhibitors by limiting fibroblast proliferation (and hence collagen production), and therefore it would reduce fibrosis in patients with hypertension.
Hypertension 2001 Mar
PMID:Effect of N-acetyl-seryl-aspartyl-lysyl-proline on DNA and collagen synthesis in rat cardiac fibroblasts. 1124 3

We evaluated the effects of cilnidipine, a long-acting Ca(2+) channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ETA receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ETA receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ETA receptor expression in the left ventricle.
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PMID:Effects of cilnidipine on nitric oxide and endothelin-1 expression and extracellular signal-regulated kinase in hypertensive rats. 1143 Sep 25

Vascular smooth muscle cell (VSMC) proliferation is a prominent feature of the atherosclerotic process that occurs after endothelial injury. Although a vascular wall kallikrein-kinin system has been described, its contribution to vascular disease remains undefined. Because the B(1)-kinin receptor subtype (B1KR) is induced in VSMCs only in response to injury, we hypothesize that this receptor may be mediating critical events in the progression of vascular disease. In the present study, we provide evidence that des-Arg(9)-bradykinin (dABK) (10(-8) M), acting through B1KR, stimulates the phosphorylation of mitogen-activated protein kinase (MAPK) (p42(mapk) and p44(mapk)). Activation of MAPK by dABK is mediated via a cholera toxin-sensitive pathway and appears to involve protein kinase C, Src kinase, and MAPK kinase. These findings demonstrate that the activation of B1KR in VSMCs leads to the generation of second messengers that converge to activate MAPK and provide a rationale to investigate the mitogenic actions of dABK in vascular injury.
Hypertension 2001 Sep
PMID:Induction of B(1)-kinin receptors in vascular smooth muscle cells: cellular mechanisms of map kinase activation. 1156 39


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