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Article ; Online: Protease-Activated Receptor 2 Controls Vascular Smooth Muscle Cell Proliferation in Cyclic AMP-Dependent Protein Kinase/Mitogen-Activated Protein Kinase Kinase 1/2-Dependent Manner.

Williams, Madison D / Bullock, Michael T / Johnson, Sean C / Holland, Nathan A / Vuncannon, Danielle M / Oswald, Joani Zary / Adderley, Shaquria P / Tulis, David A

Journal of vascular research

2023 Volume 60, Issue 4, Page(s) 213–226

Abstract: Introduction: Cardiovascular disorders are characterized by vascular smooth muscle (VSM) transition from a contractile to proliferative state. Protease-activated receptor 2 (PAR2) involvement in this phenotypic conversion remains unclear. We ... ...

Abstract	Introduction: Cardiovascular disorders are characterized by vascular smooth muscle (VSM) transition from a contractile to proliferative state. Protease-activated receptor 2 (PAR2) involvement in this phenotypic conversion remains unclear. We hypothesized that PAR2 controls VSM cell proliferation in phenotype-dependent manner and through specific protein kinases. Methods: Rat clonal low (PLo; P3-P6) and high passage (PHi; P10-P15) VSM cells were established as respective models of quiescent and proliferative cells, based on reduced PKG-1 and VASP. Western blotting determined expression of cytoskeletal/contractile proteins, PAR2, and select protein kinases. DNA synthesis and cell proliferation were measured 24-72 h following PAR2 agonism (SLIGRL; 100 nM-10 μ<sc>m</sc>) with/without PKA (PKI; 10 μ<sc>m</sc>), MEK1/2 (PD98059; 10 μ<sc>m</sc>), and PI3K (LY294002; 1 μ<sc>m</sc>) blockade. Results: PKG-1, VASP, SM22α, calponin, cofilin, and PAR2 were reduced in PHi versus PLo cells. Following PAR2 agonism, DNA synthesis and cell proliferation increased in PLo cells but decreased in PHi cells. Western analyses showed reduced PKA, MEK1/2, and PI3K in PHi versus PLo cells, and kinase blockade revealed PAR2 controls VSM cell proliferation through PKA/MEK1/2. Discussion: Findings highlight PAR2 and PAR2-driven PKA/MEK1/2 in control of VSM cell growth and provide evidence for continued investigation of PAR2 in VSM pathology.
MeSH term(s)	Rats ; Animals ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Receptor, PAR-2/genetics ; Receptor, PAR-2/metabolism ; MAP Kinase Kinase 1/metabolism ; Muscle, Smooth, Vascular/metabolism ; Cell Proliferation ; Phosphatidylinositol 3-Kinases/metabolism ; DNA/metabolism ; Cells, Cultured
Chemical Substances	Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Receptor, PAR-2 ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; DNA (9007-49-2)
Language	English
Publishing date	2023-09-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1105259-4
ISSN	1423-0135 ; 1018-1172
ISSN (online)	1423-0135
ISSN	1018-1172
DOI	10.1159/000532032
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Article ; Online: Activation of RhoA, but Not Rac1, Mediates Early Stages of S1P-Induced Endothelial Barrier Enhancement.

Zhang, Xun E / Adderley, Shaquria P / Breslin, Jerome W

PloS one

2016 Volume 11, Issue 5, Page(s) e0155490

Abstract: Compromised endothelial barrier function is a hallmark of inflammation. Rho family GTPases are critical in regulating endothelial barrier function, yet their precise roles, particularly in sphingosine-1-phosphate (S1P)-induced endothelial barrier ... ...

Abstract	Compromised endothelial barrier function is a hallmark of inflammation. Rho family GTPases are critical in regulating endothelial barrier function, yet their precise roles, particularly in sphingosine-1-phosphate (S1P)-induced endothelial barrier enhancement, remain elusive. Confluent cultures of human umbilical vein endothelial cells (HUVEC) or human dermal microvascular endothelial cells (HDMEC) were used to model the endothelial barrier. Barrier function was assessed by determining the transendothelial electrical resistance (TER) using an electrical cell-substrate impedance sensor (ECIS). The roles of Rac1 and RhoA were tested in S1P-induced barrier enhancement. The results show that pharmacologic inhibition of Rac1 with Z62954982 failed to block S1P-induced barrier enhancement. Likewise, expression of a dominant negative form of Rac1, or knockdown of native Rac1 with siRNA, failed to block S1P-induced elevations in TER. In contrast, blockade of RhoA with the combination of the inhibitors Rhosin and Y16 significantly reduced S1P-induced increases in TER. Assessment of RhoA activation in real time using a fluorescence resonance energy transfer (FRET) biosensor showed that S1P increased RhoA activation primarily at the edges of cells, near junctions. This was complemented by myosin light chain-2 phosphorylation at cell edges, and increased F-actin and vinculin near intercellular junctions, which could all be blocked with pharmacologic inhibition of RhoA. The results suggest that S1P causes activation of RhoA at the cell periphery, stimulating local activation of the actin cytoskeleton and focal adhesions, and resulting in endothelial barrier enhancement. S1P-induced Rac1 activation, however, does not appear to have a significant role in this process.
MeSH term(s)	Cardiac Myosins/metabolism ; Endothelium, Vascular/metabolism ; Gene Expression ; Gene Knockdown Techniques ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Lysophospholipids/metabolism ; Myosin Light Chains/metabolism ; Phosphorylation ; RNA Interference ; RNA, Small Interfering/genetics ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism ; rhoA GTP-Binding Protein/antagonists & inhibitors ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Lysophospholipids ; Myosin Light Chains ; RNA, Small Interfering ; myosin light chain 2 ; sphingosine 1-phosphate (26993-30-6) ; Cardiac Myosins (EC 3.6.1.-) ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2016-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0155490
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Article ; Online: Involvement of the H1 Histamine Receptor, p38 MAP Kinase, Myosin Light Chains Kinase, and Rho/ROCK in Histamine-Induced Endothelial Barrier Dysfunction.

Adderley, Shaquria P / Zhang, Xun E / Breslin, Jerome W

Microcirculation (New York, N.Y. : 1994)

2015 Volume 22, Issue 4, Page(s) 237–248

Abstract: Objective: The mechanisms by which histamine increases microvascular permeability remain poorly understood. We tested the hypothesis that H1 receptor activation disrupts the endothelial barrier and investigated potential downstream signals.: Methods: ...

Abstract	Objective: The mechanisms by which histamine increases microvascular permeability remain poorly understood. We tested the hypothesis that H1 receptor activation disrupts the endothelial barrier and investigated potential downstream signals. Methods: We used confluent EC monolayers, assessing TER as an index of barrier function. HUVEC, HCMEC, and HDMEC were compared. Receptor expression was investigated using Western blotting, IF confocal microscopy and RT-PCR. Receptor function and downstream signaling pathways were tested using pharmacologic antagonists and inhibitors, respectively. Results: We identified H1-H4 receptors on all three EC types. H1 antagonists did not affect basal TER but prevented the histamine-induced decrease in TER. Blockade of H2 or H3 attenuated the histamine response only in HDMEC, while inhibition of H4 attenuated the response only in HUVEC. Combined inhibition of both PKC and PI3K caused exaggerated histamine-induced barrier dysfunction in HDMEC, whereas inhibition of p38 MAP kinase attenuated the histamine response in all three EC types. Inhibition of RhoA, ROCK, or MLCK also prevented the histamine-induced decrease in TER in HDMEC. Conclusion: The data suggest that multiple signaling pathways contribute to histamine-induced endothelial barrier dysfunction via the H1 receptor.
MeSH term(s)	Endothelium, Vascular/metabolism ; Endothelium, Vascular/pathology ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; MAP Kinase Signaling System ; Myosin-Light-Chain Kinase/metabolism ; Receptors, Histamine H1/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/metabolism ; rho-Associated Kinases/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Receptors, Histamine H1 ; RHOA protein, human (124671-05-2) ; rho-Associated Kinases (EC 2.7.11.1) ; Myosin-Light-Chain Kinase (EC 2.7.11.18) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2015-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1217758-1
ISSN	1549-8719 ; 1073-9688
ISSN (online)	1549-8719
ISSN	1073-9688
DOI	10.1111/micc.12189
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Zs.A 4187: Show issues

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Article ; Online: Activation of RhoA, but Not Rac1, Mediates Early Stages of S1P-Induced Endothelial Barrier Enhancement.

Xun E Zhang / Shaquria P Adderley / Jerome W Breslin

PLoS ONE, Vol 11, Iss 5, p e

2016 Volume 0155490

Abstract	Compromised endothelial barrier function is a hallmark of inflammation. Rho family GTPases are critical in regulating endothelial barrier function, yet their precise roles, particularly in sphingosine-1-phosphate (S1P)-induced endothelial barrier enhancement, remain elusive. Confluent cultures of human umbilical vein endothelial cells (HUVEC) or human dermal microvascular endothelial cells (HDMEC) were used to model the endothelial barrier. Barrier function was assessed by determining the transendothelial electrical resistance (TER) using an electrical cell-substrate impedance sensor (ECIS). The roles of Rac1 and RhoA were tested in S1P-induced barrier enhancement. The results show that pharmacologic inhibition of Rac1 with Z62954982 failed to block S1P-induced barrier enhancement. Likewise, expression of a dominant negative form of Rac1, or knockdown of native Rac1 with siRNA, failed to block S1P-induced elevations in TER. In contrast, blockade of RhoA with the combination of the inhibitors Rhosin and Y16 significantly reduced S1P-induced increases in TER. Assessment of RhoA activation in real time using a fluorescence resonance energy transfer (FRET) biosensor showed that S1P increased RhoA activation primarily at the edges of cells, near junctions. This was complemented by myosin light chain-2 phosphorylation at cell edges, and increased F-actin and vinculin near intercellular junctions, which could all be blocked with pharmacologic inhibition of RhoA. The results suggest that S1P causes activation of RhoA at the cell periphery, stimulating local activation of the actin cytoskeleton and focal adhesions, and resulting in endothelial barrier enhancement. S1P-induced Rac1 activation, however, does not appear to have a significant role in this process.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Lymphatic Vessel Network Structure and Physiology.

Breslin, Jerome W / Yang, Ying / Scallan, Joshua P / Sweat, Richard S / Adderley, Shaquria P / Murfee, Walter L

Comprehensive Physiology

2018 Volume 9, Issue 1, Page(s) 207–299

Abstract: The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains ... ...

Abstract	The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
MeSH term(s)	Animals ; Homeostasis ; Humans ; Lymphatic System/anatomy & histology ; Lymphatic System/growth & development ; Lymphatic System/physiology
Language	English
Publishing date	2018-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c180015
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Article ; Online: Histamine activates p38 MAP kinase and alters local lamellipodia dynamics, reducing endothelial barrier integrity and eliciting central movement of actin fibers.

Adderley, Shaquria P / Lawrence, Curtis / Madonia, Eyong / Olubadewo, Joseph O / Breslin, Jerome W

American journal of physiology. Cell physiology

2015 Volume 309, Issue 1, Page(s) C51–9

Abstract: The role of the actin cytoskeleton in endothelial barrier function has been debated for nearly four decades. Our previous investigation revealed spontaneous local lamellipodia in confluent endothelial monolayers that appear to increase overlap at ... ...

Abstract	The role of the actin cytoskeleton in endothelial barrier function has been debated for nearly four decades. Our previous investigation revealed spontaneous local lamellipodia in confluent endothelial monolayers that appear to increase overlap at intercellular junctions. We tested the hypothesis that the barrier-disrupting agent histamine would reduce local lamellipodia protrusions and investigated the potential involvement of p38 mitogen-activated protein (MAP) kinase activation and actin stress fiber formation. Confluent monolayers of human umbilical vein endothelial cells (HUVEC) expressing green fluorescent protein-actin were studied using time-lapse fluorescence microscopy. The protrusion and withdrawal characteristics of local lamellipodia were assessed before and after addition of histamine. Changes in barrier function were determined using electrical cell-substrate impedance sensing. Histamine initially decreased barrier function, lamellipodia protrusion frequency, and lamellipodia protrusion distance. A longer time for lamellipodia withdrawal and reduced withdrawal distance and velocity accompanied barrier recovery. After barrier recovery, a significant number of cortical fibers migrated centrally, eventually resembling actin stress fibers. The p38 MAP kinase inhibitor SB203580 attenuated the histamine-induced decreases in barrier function and lamellipodia protrusion frequency. SB203580 also inhibited the histamine-induced decreases in withdrawal distance and velocity, and the subsequent actin fiber migration. These data suggest that histamine can reduce local lamellipodia protrusion activity through activation of p38 MAP kinase. The findings also suggest that local lamellipodia have a role in maintaining endothelial barrier integrity. Furthermore, we provide evidence that actin stress fiber formation may be a reaction to, rather than a cause of, reduced endothelial barrier integrity.
MeSH term(s)	Cell Movement/drug effects ; Cells, Cultured ; Electric Impedance ; Enzyme Activation ; Histamine/pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/enzymology ; Humans ; Microscopy, Fluorescence ; Microscopy, Video ; Permeability ; Protein Kinase Inhibitors/pharmacology ; Pseudopodia/drug effects ; Pseudopodia/enzymology ; Signal Transduction/drug effects ; Stress Fibers/drug effects ; Stress Fibers/enzymology ; Time Factors ; Time-Lapse Imaging ; Transfection ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Protein Kinase Inhibitors ; Histamine (820484N8I3) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2015-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Video-Audio Media
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00096.2015
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Article ; Online: Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells.

Adderley, Shaquria P / Joshi, Chintamani N / Martin, Danielle N / Tulis, David Anthony

Frontiers in pharmacology

2012 Volume 3, Page(s) 10

Abstract: BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator- ... ...

Abstract	BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASP(Ser239) and VASP(Ser157), respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASP(Ser239) but inhibited phosphorylation at VASP(Ser157). Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASP(Ser239) and VASP(Ser157), whereas PDE5 inhibition potentiated BAY-mediated increases only at VASP(Ser157). In comparison, 8Br-cGMP increased phosphorylation at VASP(Ser239) and VASP(Ser157) which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASP(Ser239) phosphorylation and inhibition of PDE3 increased phosphorylation at VASP(Ser239), while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASP(Ser157) phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.
Language	English
Publishing date	2012-02-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812 ; 1663-9812
ISSN (online)	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2012.00010
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Article: Regulation of cAMP by phosphodiesterases in erythrocytes.

Adderley, Shaquria P / Sprague, Randy S / Stephenson, Alan H / Hanson, Madelyn S

Pharmacological reports : PR

2010 Volume 62, Issue 3, Page(s) 475–482

Abstract: The erythrocyte, a cell responsible for carrying and delivering oxygen in the body, has often been regarded as simply a vehicle for the circulation of hemoglobin. However, it has become evident that this cell also participates in the regulation of ... ...

Abstract	The erythrocyte, a cell responsible for carrying and delivering oxygen in the body, has often been regarded as simply a vehicle for the circulation of hemoglobin. However, it has become evident that this cell also participates in the regulation of vascular caliber in the microcirculation via release of the potent vasodilator, adenosine triphosphate (ATP). The regulated release of ATP from erythrocytes occurs via a defined signaling pathway and requires increases in cyclic 3',5'- adenosine monophosphate (cAMP). It is well recognized that cAMP is a critical second messenger in diverse signaling pathways. In all cells increases in cAMP are localized and regulated by the activity of phosphodiesterases (PDEs). In erythrocytes activation of either beta adrenergic receptors (beta(2)AR) or the prostacyclin receptor (IPR) results in increases in cAMP and ATP release. Receptor-mediated increases in cAMP are tightly regulated by distinct PDEs associated with each signaling pathway as shown by the finding that selective inhibitors of the PDEs localized to each pathway potentiate both increases in cAMP and ATP release. Here we review the profile of PDEs identified in erythrocytes, their association with specific signaling pathways and their role in the regulation of ATP release from these cells. Understanding the contribution of PDEs to the control of ATP release from erythrocytes identifies this cell as a potential target for the development of drugs for the treatment of vascular disease.
MeSH term(s)	Animals ; Cell Compartmentation ; Cyclic AMP/blood ; Cyclic AMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 1/blood ; Cyclic Nucleotide Phosphodiesterases, Type 1/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 2/blood ; Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3/blood ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/blood ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Erythrocytes/enzymology ; Erythrocytes/metabolism ; Humans ; Phosphoric Diester Hydrolases/blood ; Phosphoric Diester Hydrolases/metabolism ; Rabbits ; Signal Transduction
Chemical Substances	Cyclic AMP (E0399OZS9N) ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; Cyclic Nucleotide Phosphodiesterases, Type 1 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 2 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; PDE2A protein, human (EC 3.1.4.17) ; PDE3A protein, human (EC 3.1.4.17) ; PDE3B protein, human (EC 3.1.4.17) ; PDE4A protein, human (EC 3.1.4.17)
Language	English
Publishing date	2010-07-14
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2186248-5
ISSN	1734-1140
ISSN	1734-1140
DOI	10.1016/s1734-1140(10)70303-0
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Article ; Online: Soluble guanylyl cyclase-activated cyclic GMP-dependent protein kinase inhibits arterial smooth muscle cell migration independent of VASP-serine 239 phosphorylation.

Holt, Andrew W / Martin, Danielle N / Shaver, Patti R / Adderley, Shaquria P / Stone, Joshua D / Joshi, Chintamani N / Francisco, Jake T / Lust, Robert M / Weidner, Douglas A / Shewchuk, Brian M / Tulis, David A

Cellular signalling

2016 Volume 28, Issue 9, Page(s) 1364–1379

Abstract: Coronary artery disease (CAD) accounts for over half of all cardiovascular disease-related deaths. Uncontrolled arterial smooth muscle (ASM) cell migration is a major component of CAD pathogenesis and efforts aimed at attenuating its progression are ... ...

Abstract	Coronary artery disease (CAD) accounts for over half of all cardiovascular disease-related deaths. Uncontrolled arterial smooth muscle (ASM) cell migration is a major component of CAD pathogenesis and efforts aimed at attenuating its progression are clinically essential. Cyclic nucleotide signaling has long been studied for its growth-mitigating properties in the setting of CAD and other vascular disorders. Heme-containing soluble guanylyl cyclase (sGC) synthesizes cyclic guanosine monophosphate (cGMP) and maintains vascular homeostasis predominantly through cGMP-dependent protein kinase (PKG) signaling. Considering that reactive oxygen species (ROS) can interfere with appropriate sGC signaling by oxidizing the cyclase heme moiety and so are associated with several CVD pathologies, the current study was designed to test the hypothesis that heme-independent sGC activation by BAY 60-2770 (BAY60) maintains cGMP levels despite heme oxidation and inhibits ASM cell migration through phosphorylation of the PKG target and actin-binding vasodilator-stimulated phosphoprotein (VASP). First, using the heme oxidant ODQ, cGMP content was potentiated in the presence of BAY60. Using a rat model of arterial growth, BAY60 significantly reduced neointima formation and luminal narrowing compared to vehicle (VEH)-treated controls. In rat ASM cells BAY60 significantly attenuated cell migration, reduced G:F actin, and increased PKG activity and VASP Ser239 phosphorylation (pVASP·S239) compared to VEH controls. Site-directed mutagenesis was then used to generate overexpressing full-length wild type VASP (FL-VASP/WT), VASP Ser239 phosphorylation-mimetic (FL-VASP/239D) and VASP Ser239 phosphorylation-resistant (FL-VASP/239A) ASM cell mutants. Surprisingly, FL-VASP/239D negated the inhibitory effects of FL-VASP/WT and FL-VASP/239A cells on migration. Furthermore, when FL-VASP mutants were treated with BAY60, only the FL-VASP/239D group showed reduced migration compared to its VEH controls. Intriguingly, FL-VASP/239D abrogated the stimulatory effects of FL-VASP/WT and FL-VASP/239A cells on PKG activity. In turn, pharmacologic blockade of PKG in the presence of BAY60 reversed the inhibitory effect of BAY60 on naïve ASM cell migration. Taken together, we demonstrate for the first time that BAY60 inhibits ASM cell migration through cGMP/PKG/VASP signaling yet through mechanisms independent of pVASP·S239 and that FL-VASP overexpression regulates PKG activity in rat ASM cells. These findings implicate BAY60 as a potential pharmacotherapeutic agent against aberrant ASM growth disorders such as CAD and also establish a unique mechanism through which VASP controls PKG activity.
MeSH term(s)	Actins/metabolism ; Animals ; Arteries/cytology ; Benzoates/pharmacology ; Biphenyl Compounds/pharmacology ; Cell Adhesion Molecules/metabolism ; Cell Movement/drug effects ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Enzyme Activation/drug effects ; Hydrocarbons, Fluorinated/pharmacology ; Male ; Microfilament Proteins/metabolism ; Mutagenesis, Site-Directed ; Mutant Proteins/metabolism ; Myocytes, Smooth Muscle/cytology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/enzymology ; Oxidation-Reduction ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Phosphoserine ; Rats, Sprague-Dawley ; Reproducibility of Results ; Soluble Guanylyl Cyclase/metabolism ; Vascular Remodeling/drug effects
Chemical Substances	4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid ; Actins ; Benzoates ; Biphenyl Compounds ; Cell Adhesion Molecules ; Hydrocarbons, Fluorinated ; Microfilament Proteins ; Mutant Proteins ; Phosphoproteins ; vasodilator-stimulated phosphoprotein ; Phosphoserine (17885-08-4) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Soluble Guanylyl Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2016-06-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2016.06.012
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Article ; Online: Identification of cytosolic phosphodiesterases in the erythrocyte: a possible role for PDE5.

Adderley, Shaquria P / Thuet, Kelly M / Sridharan, Meera / Bowles, Elizabeth A / Stephenson, Alan H / Ellsworth, Mary L / Sprague, Randy S

Medical science monitor : international medical journal of experimental and clinical research

2011 Volume 17, Issue 5, Page(s) CR241–7

Abstract: Background: Within erythrocytes (RBCs), cAMP levels are regulated by phosphodiesterases (PDEs). Increases in cAMP and ATP release associated with activation of β-adrenergic receptors (βARs) and prostacyclin receptors (IPRs) are regulated by PDEs 2, 4 ... ...

Abstract	Background: Within erythrocytes (RBCs), cAMP levels are regulated by phosphodiesterases (PDEs). Increases in cAMP and ATP release associated with activation of β-adrenergic receptors (βARs) and prostacyclin receptors (IPRs) are regulated by PDEs 2, 4 and PDE 3, respectively. Here we establish the presence of cytosolic PDEs in RBCs and determine a role for PDE5 in regulating levels of cGMP. Material/methods: Purified cytosolic proteins were obtained from isolated human RBCs and western analysis was performed using antibodies against PDEs 3A, 4 and 5. Rabbit RBCs were incubated with dbcGMP, a cGMP analog, to determine the effect of cGMP on cAMP levels. To determine if cGMP affects receptor-mediated increases in cAMP, rabbit RBCs were incubated with dbcGMP prior to addition of isoproterenol (ISO), a βAR receptor agonist. To demonstrate that endogenous cGMP produces the same effect, rabbit and human RBCs were incubated with SpNONOate (SpNO), a nitric oxide donor, and YC1, a direct activator of soluble guanylyl cyclase (sGC), in the absence and presence of a selective PDE5 inhibitor, zaprinast (ZAP). Results: Western analysis identified PDEs 3A, 4D and 5A. dbcGMP produced a concentration dependent increase in cAMP and ISO-induced increases in cAMP were potentiated by dbcGMP. In addition, incubation with YC1 and SpNO in the presence of ZAP potentiated βAR-induced increases in cAMP. Conclusions: PDEs 2, 3A and 5 are present in the cytosol of human RBCs. PDE5 activity in RBCs regulates cGMP levels. Increases in intracellular cGMP augment cAMP levels. These studies suggest a novel role for PDE5 in erythrocytes.
MeSH term(s)	Animals ; Cyclic AMP/metabolism ; Cyclic GMP/pharmacology ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Cytosol/drug effects ; Cytosol/enzymology ; Erythrocytes/cytology ; Erythrocytes/drug effects ; Erythrocytes/enzymology ; Humans ; Isoenzymes/metabolism ; Isoproterenol/pharmacology ; Male ; Phosphodiesterase Inhibitors/pharmacology ; Purinones/pharmacology ; Rabbits ; Spermine/analogs & derivatives ; Spermine/pharmacology ; Vinca Alkaloids/pharmacology
Chemical Substances	Isoenzymes ; Phosphodiesterase Inhibitors ; Purinones ; Vinca Alkaloids ; spermine nitric oxide complex (136587-13-8) ; Spermine (2FZ7Y3VOQX) ; vinpocetine (543512OBTC) ; Cyclic AMP (E0399OZS9N) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; zaprinast (GXT25D5DS0) ; Cyclic GMP (H2D2X058MU) ; Isoproterenol (L628TT009W)
Language	English
Publishing date	2011-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1439041-3
ISSN	1643-3750 ; 1234-1010
ISSN (online)	1643-3750
ISSN	1234-1010
DOI	10.12659/msm.881763
Database	MEDical Literature Analysis and Retrieval System OnLINE

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