Abstract 2579: tPA Contributes To Aggravation of Endothelin and Thromboxane Induced Cerebrovasoconstriction After Hypoxia/Ischemia Through Upregulation of ERK MAPK

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
William Armstead ◽  
Heather Kaczynski ◽  
John Riley ◽  
Douglas Cines ◽  
Abd Al-Roof Higazi
Keyword(s):  
Mitogen Activated Protein Kinase ◽  
Tissue Type ◽  
Cranial Window ◽  
Pial Artery ◽  
Erk Mapk ◽  
Cerebral Vasoconstriction ◽  
Type Plasminogen Activator ◽  
Hypoxia Ischemia ◽  
Mitogen Activated Protein ◽  
Global Increase

Introduction: The sole FDA approved treatment for acute stroke is tissue type plasminogen activator (tPA). However, endogenous tPA is upregulated and potentiates impairment of pial artery dilation in response to hypotension after hypoxia/ischemia (H/I) in pigs. Mitogen activated protein kinase (MAPK), a family of at least 3 kinases, ERK, p38 and JNK, is also upregulated after H/I, with ERK contributing to vasodilator impairment. Impairment of stimulus induced vasodilation may result from tonic withdrawal and/or impairment of a vasodilator influence or upregulation of a vasoconstrictor. This study examined the effect of H/I on the vascular response to two important spasmogens released during CNS ischemic disorders, endothelin-1 (ET-1) and thromboxane, and the influence of tPA and ERK MAPK in such responses. Methods: Cerebral ischemia (20 min) was induced via global increase in intracranial pressure via saline infusion into a hollow bolt placed in the cranium (dura intact) while hypoxia (10 min, pO2 35 mm Hg) was produced by decreasing the inspired O2 via inhalation of N2. Vascular responses to topical ET-1 (10-10, 10-8 M) and U 46619 (1, 10 ng/ml) were obtained at 1h post insult. Phosphorylated and total ERK MAPK were measured by ELISA in the CSF of piglets equipped with a closed cranial window. Data (n=5) were analyzed by ANOVA, with significance at p less than 0.05. Results: H/I aggravated pial artery vasconstriction induced by ET-1 and the thromboxane mimic U 46619, which was blocked by EEIIMD, an inhibitor of PAI-1’s vascular activity and signaling of tPA, but not its fibrinolytic action, but unchanged by its inactive analogue EEIIMR. CSF ERK MAPK was increased by H/I and potentiated by tPA. The ERK MAPK antagonist U 0126 blocked H/I induced aggravation of ET-1 and U 46619 vasoconstriction. Discussion: These data indicate that H/I aggravates ET-1 and thromboxane mediated cerebral vasoconstriction through upregulation of tPA and ERK MAPK. These data suggest that thrombolytic therapy for treatment of CNS ischemic disorders can dysregulate cerebrohemodynamics by augmenting vasoconstriction induced by spasmogens co-released during CNS pathology.

PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after hypoxia/ischemia

2003 ◽  
Vol 284 (1) ◽  
pp. H101-H107 ◽  
Author(s):  
Amanda L. Jagolino ◽  
William M. Armstead
Keyword(s):  
Cerebrospinal Fluid ◽  
Protein Tyrosine Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Orphanin Fq ◽  
Sham Control ◽  
Mapk Activation ◽  
Cranial Window ◽  
Hypoxia Ischemia ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

This study characterized the contributions of protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of hypercapnic pial artery dilation (PAD) after hypoxia/ischemia (H/I) in piglets equipped with a closed cranial window. NOC/oFQ (10−10 M cerebrospinal fluid H/I concentration) impaired hypercapnic PAD (21 ± 2% vs. 13 ± 1%). Coadministration of either of the PTK inhibitors genistein or tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10−10 M) partially prevented the inhibition of hypercapnic PAD compared with that observed in their absence (21 ± 2% vs. 17 ± 1% for genistein). After exposure to H/I, PAD in response to hypercapnia was impaired, but pretreatment with either genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such impairment (17 ± 1% vs. 4 ± 1% vs. 9 ± 1% for sham control, H/I, and H/I + genistein pretreatment, respectively). These data show that PTK and MAPK activation contribute to NOC/oFQ-induced impairment of hypercapnic PAD. These data suggest that activation of PTK and MAPK is also involved in the mechanism by which NOC/oFQ impairs hypercapnic PAD after H/I.

Inhibition of miR-200c Expression Promotes Activation of Extracellular Signal-Regulated Kinase (ERK)/ Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway and Inhibits Osteogenic Differentiation in Osteoporosis Mice

2020 ◽  
Vol 10 (2) ◽  
pp. 163-168
Author(s):  
Sheng Wang ◽  
Zhonghan Min ◽  
Run Gu ◽  
Zhongwei Yu ◽  
Pingquan Chen ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Bone Diseases ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Erk Mapk ◽  
Mitogen Activated Protein ◽  
Marrow Mesenchymal Stem Cells ◽  
Sirna Group

During OP bone metabolism, activated MAPK signaling can promote the proliferation and differentiation of osteoclasts. miRNAs involve in bone diseases. Our study aimed to evaluate miR-200c’s effect on ERK/MAPK signaling pathway in OP. miR-200c expression in OP mice and normal mice was detected by qPCR. BMSCs were cultured and transfected with siRNA to establish a miR-200c knockout model. Flow cytometry was used to detect cell apoptosis and ERK/MAPK signaling protein was detected by Western blot. miR-200c expression in OP mice was significantly lower than that in normal mice. Bone marrow mesenchymal stem cells (BMSCs) contain a large amount of siRNA particles under a fluorescence microscope. siRNA transfection can effectively inhibit miR-200c expression without difference of BMSCs apoptosis between miR-200c siRNA group and NC group. However, ERK1/2 and P38 expression in experimental group were significantly higher than those in NC siRNA group with reduced ALP activity. In addition, BMSCs osteogenic differentiation was further diminished when miR-200c expression was inhibited. miR-200c expression is lower in OP mice. miR-200c siRNA inhibits BMSCs osteogenic differentiation via ERK/MAPK signaling, thereby promoting OP progression.

The Changes of Tissue-Type Plasminogen Activator and Matrix Metalloproteinases in Neonatal Mice with Hypoxic-Ischemic Encephalopathy

2012 ◽  
Vol 195-196 ◽  
pp. 447-451
Author(s):  
Jian Wen Xu ◽  
Wei Wang ◽  
Xiao Zhen Zhao ◽  
Geng Zhang ◽  
Juan Bing Wei
Keyword(s):  
Matrix Metalloproteinases ◽  
Basement Membrane ◽  
Plasminogen Activator ◽  
Hypoxic Ischemic Encephalopathy ◽  
Tissue Type ◽  
Control Group ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Hypoxia Ischemia ◽  
Ischemic Encephalopathy

Fetal distress and neonatal asphyxia are key factors which result in neonatal hypoxic-ischemic encephalopathy (HIE). There is growing evidence that tissue-type plasminogen activator (TPA) and matrix metalloproteinases (MMPs) may be involved in extracellular matrix (ECM) degradation in the central nervous system. In this study, the transmission electron microscope was used to observe the growth and development characteristics of the blood-brain barrier (BBB), follow by the activity of TPA and the expression of MMPs in HIE model were detected. The asphyxia in female mice within the last day of gestation was produced by a delayed cesarean section. The experiment was designed for 1 control group and 2 asphyctic groups (15min and 30min), then the activities of TPA and expression of MMPs were detected separately. The results showed that the BBB was not fully developed in newborns, their brain microvascular endothelial cells were not surrounded with intact basement membrane and only had discontinuous basement membrane-like materials of varying thickness. The activity of TPA and the expression of MMPs of brain increased after hypoxia-ischemia in vivo. Based on these findings we concluded that the basement membrane at the BBB was a weak link in the brain, TPA and MMPs could degrade components of the ECM. So these enzymes increased after hypoxia-ischemia might be able to attack the basement membrane of microvessels, then open the BBB and induce the cerebral edema.

scholarly journals Activation of the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathway by Conventional, Novel, and Atypical Protein Kinase C Isotypes

1998 ◽  
Vol 18 (2) ◽  
pp. 790-798 ◽  
Author(s):  
Dorothee C. Schönwasser ◽  
Richard M. Marais ◽  
Christopher J. Marshall ◽  
Peter J. Parker
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Erk Mapk ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Stimulation Of

ABSTRACT Phorbol ester treatment of quiescent Swiss 3T3 cells leads to cell proliferation, a response thought to be mediated by protein kinase C (PKC), the major cellular receptor for this class of agents. We demonstrate here that this proliferation is dependent on the activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade. It is shown that dominant-negative PKC-α inhibits stimulation of the ERK/MAPK pathway by phorbol esters in Cos-7 cells, demonstrating a role for PKC in this activation. To assess the potential specificity of PKC isotypes mediating this process, constitutively active mutants of six PKC isotypes (α, β1, δ, ɛ, η, and ζ) were employed. Transient transfection of these PKC mutants into Cos-7 cells showed that members of all three groups of PKC (conventional, novel, and atypical) are able to activate p42 MAPK as well as its immediate upstream activator, the MAPK/ERK kinase MEK-1. At the level of Raf, the kinase that phosphorylates MEK-1, the activation cascade diverges; while conventional and novel PKCs (isotypes α and η) are potent activators of c-Raf1, atypical PKC-ζ cannot increase c-Raf1 activity, stimulating MEK by an independent mechanism. Stimulation of c-Raf1 by PKC-α and PKC-η was abrogated for RafCAAX, which is a membrane-localized, partially active form of c-Raf1. We further established that activation of Raf is independent of phosphorylation at serine residues 259 and 499. In addition to activation, we describe a novel Raf desensitization induced by PKC-α, which acts to prevent further Raf stimulation by growth factors. The results thus demonstrate a necessary role for PKC and p42 MAPK activation in 12-O-tetradecanoylphorbol-13-acetate induced mitogenesis and provide evidence for multiple PKC controls acting on this MAPK cascade.

scholarly journals PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

2010 ◽  
Vol 299 (1) ◽  
pp. H76-H80 ◽  
Author(s):  
William M. Armstead ◽  
John Riley ◽  
J. Willis Kiessling ◽  
Douglas B. Cines ◽  
Abd Al-Roof Higazi
Keyword(s):  
Plasminogen Activator ◽  
P38 Mapk ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Cerebral Hypoxia ◽  
Plasminogen Activator Inhibitor 1 ◽  
Cranial Window ◽  
Type Plasminogen Activator ◽  
Sb 203580 ◽  
Activator Inhibitor

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery, or postdelivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator. H/I impairs pial artery dilation (PAD) induced by hypercapnia and hypotension, the impairment aggravated by type plasminogen activator and attenuated by the plasminogen activator inhibitor-1-derived peptide EEIIMD. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is upregulated after H/I and ERK contribute to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in the impairment of dilation post-H/I in pigs equipped with a closed cranial window and the relationship between alterations in MAPK isoforms and EEIIMD-mediated cerebrovascular protection. Cerebrospinal fluid-phosphorylated (activated) p38 MAPK, but not JNK MAPK, was increased after H/I, an effect potentiated by intravenous EEIIMD administered 1 h postinjury. PAD in response to hypercapnia and hypotension was blunted by H/I, but dilation was maintained by EEIIMD. PAD was further impaired by the p38 antagonist SB-203580 but unchanged by the JNK antagonist SP-600125. Isoproterenol-induced PAD was unchanged by H/I, EEIIMD, SB-203580, and SP-600125. These data indicate that postinjury treatment with EEIIMD attenuated impaired cerebrovasodilation post-H/I by upregulating p38 but not JNK. These data suggest that plasminogen activator inhibitor-1-based peptides and other approaches to upregulate p38 may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy for diverse central nervous system disorders associated with H/I.

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