Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in angiopoietin-1 (Ang-1)-induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 microM) and apocynin (200 microM) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although Ang-1 stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells, the responses were strikingly suppressed in cells from the p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.
 ...
PMID:Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. 1667 92

Angiopoietins are ligands for endothelial cell-specific Tie-2 receptors. Whereas angiopoietin-1 (Ang-1) activates these receptors and promotes cell survival, migration, and sprouting, little information is available regarding how Ang-2 influences these cells. In this study, we evaluated signaling pathways and biological effects of physiological concentrations of Ang-2 in cultured human umbilical vein endothelial cells. Ang-2 at 150 and 300 ng/ml elicited a transient (reaching peak values within 15 min of exposure) increase in the phosphorylation of Tie-2 receptors, protein kinase B (Akt), ERK1/2, and p38 members of the mitogen-activated protein kinases. However, unlike Ang-1, Ang-2 significantly inhibited JNK/SAPK phosphorylation. When vascular endothelial growth factor (VEGF) was present along with Ang-2, ERK1/2 phosphorylation was inhibited, whereas augmentation of Ang-1-induced ERK1/2 phosphorylation was triggered by VEGF. Ang-2 treatment had no effect on cell migration and in vitro wound healing but significantly attenuated serum deprivation-induced apoptosis and promoted survival. These effects were completely reversed by phosphatidylinositol 3 (PI3)-kinase and ERK1/2 inhibitors but were augmented by an inhibitor of the p38 pathway. These results suggest that Ang-2 promotes endothelial cell survival through the ERK1/2 and PI3-kinase pathways and that this angiopoietin is not a strong promoter of endothelial cell migration. We also conclude that the nature of interactions in terms of ERK1/2 activation between Ang-2 and VEGF is different from that of Ang-1 and VEGF.
 ...
PMID:Signaling and regulation of endothelial cell survival by angiopoietin-2. 1671 55

Angiopoietin-1 (Ang1) mediates angiogenesis by enhancing endothelial cell survival and migration. It is also known that Ang1 activates Tie2, an endothelial-specific tyrosine kinase receptor, but the molecular mechanism of this process is not clear. In this study, we investigated whether reactive oxygen species (ROS) production plays a role in Ang1-mediated angiogenesis. We found that human umbilical vein endothelial cells treated with Ang1 produce ROS transiently, which was suppressed by NADPH oxidase inhibitor, diphenylene-iodonium chloride, and rotenone. The Ang1-induced ROS was identified as hydrogen peroxide (H2O2) using adenovirus-catalase infection. Removal of H2O2 by adenovirus-catalase significantly suppressed Ang1-induced in vitro endothelial cell migration, in vivo tubule formation and angiogenesis, and activation of p44/42 mitogen-activated protein kinase (MAPK), involved in cell migration, and delayed the deactivation of Akt phosphorylation involved in cell survival. Supporting to in vitro data, Ang1-induced vascular remodeling in catalase (-/-) mice was more prominent than in catalase (+/+) mice: Ang1-induced increases of the diameter of terminal arterioles and the postcapillary venules in catalase (-/-) mice were significant compared with catalase (+/+) mice. These results show that Ang1-induced H2O2 plays an important role in Ang1-mediated angiogenesis by modulating p44/42 MAPK activity.
 ...
PMID:Hydrogen peroxide produced by angiopoietin-1 mediates angiogenesis. 1677 90

Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair as well as in the various pathophysiologies such as ischemic heart and limb diseases and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H(2)O(2) function as signaling molecules in many aspects of growth factor-mediated responses including angiogenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor and stimulates proliferation, migration, and tube formation of endothelial cells (ECs) primarily through the VEGF receptor type2 (VEGR2, KDR/Flk1). VEGF binding initiates autophosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt, and eNOS in ECs, thereby stimulating angiogenesis. The major source of ROS in EC is a NADPH oxidase which consists of Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1. ROS derived from this enzyme stimulate diverse redox signaling pathways leading to angiogenesis-related gene induction as well as EC migration and proliferation, which may contribute to postnatal angiogenesis in vivo. The aim of this review is to provide an overview of the recent progress on the emerging area of the role of ROS derived from NADPH oxidase and redox signaling in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for treatment of angiogenesis-dependent cardiovascular diseases and for promoting angiogenesis in ischemic limb and heart diseases.
 ...
PMID:Redox signaling in angiogenesis: role of NADPH oxidase. 1678 92

Both podocytes and glomerular endothelial cells (GEN) are postulated to play important roles in the progression and potential regression of glomerulosclerosis. Inhibition of angiotensin is crucial in treatment of chronic kidney disease, presumably via effects on BP and extracellular matrix. This study aimed to investigate how angiotensin inhibition altered the interactions between podocytes and GEN. The effects of supernatants from primary cultured mouse podocytes, before or after sublethal injury by puromycin aminonucleoside, in the presence or absence of angiotensin type 1 receptor blocker (ARB), on GEN sprouting and growth were assessed. Supernatant from normal podocytes significantly increased GEN sprouting, whereas puromycin aminonucleoside-injured podocyte supernatant decreased these GEN responses. These effects were linked to decreased vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) protein from injured podocytes. This downregulation of VEGF-A and Ang-1 protein was reversed when injured podocytes were treated with ARB. Inhibition of VEGF-A or Ang-1 prevented this restored response by ARB. Activation of intracellular kinases (p38, extracellular signal-regulated kinase, and AKT) was suppressed in GEN that were treated with medium from injured podocytes but restored by medium from ARB-treated injured podocytes. Therefore, injured podocytes are ineffective in promoting GEN sprouting, and this effect is reversed by ARB treatment of the injured podocyte. These data support the idea that ARB effects on podocytes may mediate capillary remodeling in vivo.
 ...
PMID:Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial cell growth. 1679 May 14

The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF)165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activation, as comparable effects were seen on TPA-induced ERK1/2 phosphorylation. Similar to previously described angiostatic agents like angiopoietin-1 or the 16-kDa prolactin fragment, Eap blockage of the Ras/Raf/MEK/ERK cascade was localized by pull-down assay at the level of Ras activation. Eap's combined anti-inflammatory and antiangiogenic properties render this bacterial protein not only an important virulence factor during S. aureus infection but open new perspectives for therapeutic applications in pathological neovascularization.
 ...
PMID:The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation. 1707 91

Ozone has potent oxidizing properties, and exposure to ozone causes airway hyper-responsiveness (AHR) and lung inflammation. We determined the importance of c-Jun NH(2) terminal kinase (JNK), a member of the mitogen-activated protein kinase pathway, in ozone-induced AHR and inflammation. SP600125 [anthra[1,9-cd] pyrazol-6 (2H)-one], a specific JNK inhibitor (30 mg/kg) or vehicle, was administered by intraperitoneal injection before and after ozone exposure (3 ppm for 3 h). SP600125 significantly reduced total cells, and neutrophils in bronchoalveolar fluid recovered at 20 to 24 h after exposure and inhibited ozone-induced AHR. Ozone exposure induced activation of JNK in the lung as measured by the expression of phosphorylated-c-Jun, an effect abolished by SP600125. Gene-microarray analysis revealed that ozone increased the expression of over 400 genes by more than 2-fold, including interleukin-6 (IL-6), CXCL1 (keratinocyte cytokine), and CCL2 (monocyte chemoattractant protein-1). SP600125 modulated the expression of a subset of 29 ozone-induced genes; IL-6 and CCL2 expression were further increased, whereas the expression of metallothionein 1, hemopexin, and mitogen-activated 3 kinase 6 was decreased in SP600125-treated ozone-exposed mice. Changes in mRNA for IL-6, CXCL1, and CCL2 were confirmed by real-time polymerase chain reaction. Ozone also decreased the expression of over 500 genes, with the most potent effect on angiopoietin-1. SP600125 modulated the expression of 15 of these genes, and in particular, SP600125 reversed ozone-induced decrease in expression of the redox-sensitive transcription factor, hypoxia-induced factor-1alpha. This study highlights an important role for JNK in response to oxidative stress through modulation of specific inflammatory and redox mediators. Inhibition of JNK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and AHR.
 ...
PMID:Attenuation of ozone-induced airway inflammation and hyper-responsiveness by c-Jun NH2 terminal kinase inhibitor SP600125. 1746 Jan 51

Curcumin is known to be a potent wound healer. Despite this, studies on curcumin using certain model systems have shown it to be anti-angiogenic. Results of the present investigations suggest that curcumin causes opposing effects on angiogenesis in serum stimulated and unstimulated conditions. The evidence in support of this are: (a) in serum free conditions, curcumin promoted sprouting in rat aortic ring, increased vascular density in CAM and induced morphological changes indicative of angiogenic phenotype in HUVECs and rat aortic endothelial cells in culture, (b) increased the expression of biochemical markers of angiogenesis such as CD 31, E-selectin, VEGF and VEGFR-2 in HUVECs on treatment with curcumin, and (c) supplementation of curcumin along with serum caused decrease in CD 31 and E-selectin levels, downregulation of VEGF, angiopoietin-1 and VEGFR-2 and delayed formation of capillary network-like structure. Proangiogenic effect of the individual components of the natural curcumin differed and the presence of the three components in the natural mixture has a synergistic effect. Effect of curcuminoids in the absence of serum appears to depend on VEGF as (a) anti-VEGF antibody blocked the effect of curcuminoids (b) curcuminoids caused decrease in PAR modification of VEGF increasing its biological activity. Treatment with curcuminoids in serum-free conditions resulted in activation of PI3K-Akt pathway; but in serum-supplemented condition, curcuminoids caused inhibition of the MAPK pathways thereby inhibiting the expression of angiogenic phenotype. These results suggest that PI3K-Akt and MAPK pathways involved in the expression of angiogenic phenotype respond differently to the extracellular microenvironment.
 ...
PMID:Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response. 1796 May 70

Angiopoietin-1 (Ang-1), ligand for the endothelial cell-specific Tie-2 receptors, promotes migration and proliferation of endothelial cells, however, whether these effects are promoted through the release of a secondary mediator remains unclear. In this study, we assessed whether Ang-1 promotes endothelial cell migration and proliferation through the release of interleukin-8 (IL-8). Ang-1 elicited in human umbilical vein endothelial cells (HUVECs) a dose- and time-dependent increase in IL-8 production as a result of induction of mRNA and enhanced mRNA stability of IL-8 transcripts. IL-8 production is also elevated in HUVECs transduced with retroviruses expressing Ang-1. Neutralization of IL-8 in these cells with a specific antibody significantly attenuated proliferation and migration and induced caspase-3 activation. Exposure to Ang-1 triggered a significant increase in DNA binding of activator protein-1 (AP-1) to a relatively short fragment of IL-8 promoter. Upstream from the AP-1 complex, up-regulation of IL-8 transcription by Ang-1 was mediated through the Erk1/2, SAPK/JNK, and PI-3 kinase pathways, which triggered c-Jun phosphorylation on Ser63 and Ser73. These results suggest that promotion of endothelial migration and proliferation by Ang-1 is mediated, in part, through the production of IL-8, which acts in an autocrine fashion to suppress apoptosis and facilitate cell proliferation and migration.
 ...
PMID:Angiopoietin-1 promotes endothelial cell proliferation and migration through AP-1-dependent autocrine production of interleukin-8. 1825 63

Angiopoietins were thought to be endothelial cell-specific via the tie2 receptor. We showed that angiopoietin-1 (ang1) also interacts with integrins on cardiac myocytes (CMs) to increase survival. Because ang1 monomers bind and activate integrins (not tie2), we determined their function in vivo. We examined monomer and multimer expressions during physiological and pathological cardiac remodeling and overexpressed ang1 monomers in phenylephrine-induced cardiac hypertrophy. Cardiac ang1 levels (mRNA, protein) increased during postnatal development and decreased with phenylephrine-induced cardiac hypertrophy, whereas tie2 phosphorylations were unchanged. We found that most or all of the changes during cardiac remodeling were in monomers, offering an explanation for unchanged tie2 activity. Heart tissue contains abundant ang1 monomers and few multimers (Western blotting). We generated plasmids that produce ang1 monomers (ang1-256), injected them into mice, and confirmed cardiac expression (immunohistochemistry, RT-PCR). Ang1 monomers localize to CMs, smooth muscle cells, and endothelial cells. In phenylephrine-induced cardiac hypertrophy, ang1-256 reduced left ventricle (LV)/tibia ratios, fetal gene expressions (atrial and brain natriuretic peptides, skeletal actin, beta-myosin heavy chain), and fibrosis (collagen III), and increased LV prosurvival signaling (akt, MAPK(p42/44)), and AMPK(T172). However, tie2 phosphorylations were unchanged. Ang1-256 increased integrin-linked kinase, a key regulator of integrin signaling and cardiac health. Collectively, these results suggest a role for ang1 monomers in cardiac remodeling.
 ...
PMID:Integrin binding angiopoietin-1 monomers reduce cardiac hypertrophy. 1850 41


<< Previous 1 2 3 4 5 6 7 Next >>