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)

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

Studies were performed to test the hypothesis that reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) contribute to the pathogenesis of aldosterone/salt-induced renal injury. Rats were given 1% NaCl to drink and were treated with one of the following combinations for 6 weeks: vehicle (0.5% ethanol, SC, n=6); aldosterone (0.75 microg/H, SC, n=8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, n=8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking solution, n=8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH2-terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot analysis. Aldosterone-infused rats showed higher systolic blood pressure (165+/-5 mm Hg) and urinary excretion of protein (106+/-24 mg/d) than vehicle-infused rats (118+/-3 mm Hg and 10+/-3 mg/d). Renal cortical mRNA expression of p22phox, Nox-4, and gp91phox, measured by real-time polymerase chain reaction, was increased in aldosterone-infused rats by 2.3, 4.3, and 3.0-fold, respectively. Thiobarbituric acid-reactive substances (TBARS) content in renal cortex was also higher in aldosterone (0.23+/-0.02) than vehicle-infused rats (0.09+/-0.01 nmol/mg protein). ERK1/2, JNK, and BMK1 activities were significantly elevated in aldosterone-infused rats by 3.3, 2.3, and 3.0-fold, respectively, whereas p38MAPK activity was not changed. Concurrent administration of eplerenone or tempol to aldosterone-infused rats prevented the development of hypertension (127+/-2 and 125+/-5 mm Hg), and the elevations of urinary excretion of protein (10+/-2 and 9+/-2 mg/day) or TBARS contents (0.08+/-0.01 and 0.11+/-0.01 nmol/mg protein). Furthermore, eplerenone and tempol treatments normalized the activities of ERK1/2, JNK, and BMK1. These data suggest that ROS and MAPK play a role in the progression of renal injury induced by chronic elevations in aldosterone.
Hypertension 2004 Apr
PMID:Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. 1476 8

Increasing evidence indicates that aldosterone elicits vascular effects through nongenomic signaling pathways. We tested the hypothesis that aldosterone induces activation of vascular mitogen-activated protein (MAP) kinases and NADPH oxidase via c-Src-dependent mechanisms in vascular smooth muscle cells (VSMCs). Aldosterone effects on activation of c-Src, p38MAP kinase, and NADPH oxidase, and incorporation of [3H]proline, an index of collagen synthesis, were assessed in cultured rat VSMCs. Studies were performed in the absence and presence of eplerenone, a selective mineralocorticoid receptor blocker, PP2, a selective Src inhibitor, and SB212190, a selective p38MAPK inhibitor. Phosphorylation of c-Src was dose-dependently increased by aldosterone, with maximal responses obtained at 10(-7) mol/L. Aldosterone increased p38MAP kinase phosphorylation, NAD(P)H oxidase activation, and [3H]proline incorporation. These responses were abrogated by eplerenone and almost abolished by PP2. Aldosterone-stimulated incorporation of [3H]proline was significantly reduced by SB212190, indicating that p38MAP kinase plays a role in profibrotic actions of aldosterone. To unambiguously demonstrate the importance of aldosterone in c-Src signaling, VSMCs from c-Src+/+ and c-Src+/- mice were also studied. Aldosterone increased phosphorylation of c-Src, p38MAP kinase, and cortactin, a Src-specific substrate, in c-Src+/+ VSMCs, but not in c-Src-deficient cells. Taken together, our findings demonstrate that nongenomic signaling by aldosterone occurs through c-Src-dependent pathways. These processes may play an important role in profibrotic actions of aldosterone.
Hypertension 2005 Apr
PMID:Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. 1569 70

Recent studies have shown that angiotensin II type 1 (AT1) receptor-mediated Akt activation induces vascular smooth muscle cell (VSMC) dedifferentiation in vitro. However, the critical signal transductions affecting the VSMC phenotype remain unclear in vivo. We examined whether signal transduction through AT1 receptor-mediated reactive oxygen species (ROS) could regulate the VSMC phenotype in stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs were randomized and treated for 6 weeks with a vehicle, an ACE inhibitor cilazapril, or an AT1 receptor antagonist E4177. The 2 drugs showed equipotent effects on the blood pressure, aortic morphology, and collagen deposition. Both drugs also significantly reduced aortic NAD(P)H oxidase activity and p38MAPK and ERK expression, whereas p-Akt, eNOS, and SM2 were significantly increased in SHRSP aortas. Furthermore, E4177 was more effective than cilazapril at inducing VSMC differentiation by reducing NAD(P)H oxidase activity, and up-regulating p-Akt, eNOS, and SM2. Thus, an ACE inhibitor and an AT1 receptor antagonist inhibited VSMC dedifferentiation through inhibition of NAD(P)H oxidase activity and up-regulation of eNOS and Akt in SHRSP aortas, suggesting that in contrast to the in vitro experiments, AT1 receptor-mediated NAD(P)H oxidase-generated ROS, eNOS, and Akt might be crucial determinants for the VSMC phenotype in hypertension in vivo.
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PMID:Up-regulation of Akt and eNOS induces vascular smooth muscle cell differentiation in hypertension in vivo. 1577 27

Mutations in the bone morphogenetic protein type II receptor gene (BMPR2) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of BMPR2 mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38(MAPK), and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38MAPK/ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in BMPR2 are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38(MAPK)/ERK signaling, as a consequence of mutation in BMPR2, underlie the abnormal vascular cell proliferation observed in familial PAH.
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PMID:Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. 1592 25

Hypertension causes endothelial dysfunction, which plays an important role in atherogenesis. The vascular cell adhesion molecule-1 (VCAM-1) contributes to atherosclerotic lesion formation by recruiting leukocytes from blood into tissues. Tumor necrosis factor-alpha (TNFalpha) induces endothelial dysfunction and VCAM-1 expression in endothelial cells (ECs). We examined whether the cAMP-response element binding protein (CREB), a transcription factor that mediates cytokine expression and vascular remodeling, is involved in TNFalpha-induced VCAM-1 expression. TNFalpha induced phosphorylation of CREB with a peak at 15 min of stimulation in a dose-dependent manner in bovine aortic ECs. Pharmacological inhibition of p38 mitogen-activated protein kinase (p38-MAPK) inhibited TNFalpha-induced CREB phosphorylation. Adenovirus-mediated overexpression of a dominant-negative form of CREB suppressed TNFalpha-induced VCAM-1 and c-fos expression. Although activating protein 1 DNA binding activity was attenuated by overexpression of dominant negative CREB, nuclear factor-kappaB activity was not affected. Our results suggest that the p38-MAPK/CREB pathway plays a critical role in TNFalpha-induced VCAM-1 expression in vascular endothelial cells. The p38MAPK/CREB pathway may be a novel therapeutic target for the treatment of atherosclerosis.
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PMID:CAMP-response element-binding protein mediates tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in endothelial cells. 1671 52

The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.
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PMID:Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. 1687 Aug 27

3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.
Hypertension 2007 Aug
PMID:HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways. 1759 71

Mutations in the gene encoding bone morphogenetic protein (BMP) receptor type 2 (BMPR-2) have been reported in pulmonary arterial hypertension (PAH), but their functional relevance remains incompletely understood. BMP receptor expression was evaluated in human lungs and in cultured pulmonary artery smooth muscle cells (PASMCs) isolated from 19 idiopathic PAH patients and nine heritable PAH patients with demonstrated BMPR-2 mutations. BMP4-treated PASMCs were assessed for Smad and p38 mitogen-activated protein kinase (MAPK) signalling associated with mitosis and apoptosis. Lung tissue and PASMCs from heritable PAH patients presented with decreased BMPR-2 expression and variable increases in BMPR-1A and BMPR-1B expression, while a less important decreased BMPR-2 expression was observed in PASMCs from idiopathic PAH patients. Heritable PAH PASMCs showed no increased phosphorylation of Smad1/5/8 in the presence of BMP4, which actually activated the p38MAPK pathway. Individual responses varied from one mutation to another. PASMCs from PAH patients presented with an in vitro proliferative pattern, which could be inhibited by BMP4 in idiopathic PAH but not in heritable PAH. PASMCs from idiopathic PAH and more so from heritable PAH presented an inhibition of BMP4-induced apoptosis. Most heterogeneous BMPR-2 mutations are associated with defective Smad signalling compensated for by an activation of p38MAPK signalling, accounting for PASMC proliferation and deficient apoptosis.
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PMID:Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension. 1932 47

In intact vessels, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) act as an integrated system, possibly through reactive oxygen species (ROS). Using a coculture system we tested whether ECs modulate VSMC redox status by regulating activity of NAD(P)H oxidase and antioxidants. VSMC production of O(2)(*-), H(2)O(2), and NO was assessed using fluoroprobes and amplex-red. NAD(P)H oxidase subunit expression and oxidase activity were determined by Western blotting and chemiluminescence, respectively. Expression of thioredoxin, SOD, growth signaling pathways (PCNA, p21cip1, CDK4, ERK1/2, p38MAPK) was evaluated by immunoblotting. Thioredoxin activity was assessed by the insulin disulfide reduction assay. In cocultured conditions, VSMC ROS production was reduced by approximately 50% without changes in NAD(P)H oxidase expression/activity versus monoculture (P<0.05). This was associated with decreased cell growth (P<0.05). Expression of Cu/Zn SOD and thioredoxin was increased in coculture versus monoculture VSMCs (P<0.01). Pretreatment of ECs with L-NAME (NOS inhibitor), NS-398 (Cox2 inhibitor), and HET0016 (20-HETE inhibitor) did not influence VSMC ROS formation, whereas CDNB, thioredoxin reductase inhibitor, abolished ROS modulating effects of ECs. These findings indicate that in a coculture system recapitulating intact vessels, ECs negatively regulate ROS production in VSMCs through thioredoxin upregulation. Functionally this is associated with growth inhibition. The modulatory actions of ECs are independent of NOS/NO, Cox2, and HETE and do not involve NAD(P)H oxidase. Our data identify novel mechanisms whereby ECs protect against VSMC oxidative stress, a process that may be important in maintaining vascular integrity.
Hypertension 2009 Aug
PMID:Endothelial cells negatively modulate reactive oxygen species generation in vascular smooth muscle cells: role of thioredoxin. 1956 43


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