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Karsten Schrör - One of the best experts on this subject based on the ideXlab platform.

  • platelet derived microparticles stimulate coronary artery smooth muscle cell Mitogenesis by a pdgf independent mechanism
    Thrombosis Research, 2000
    Co-Authors: Artur-aron Weber, Hermann Oliver Koppen, Karsten Schrör
    Abstract:

    This study investigates the role of platelet-derived microparticles for vascular smooth muscle cell (SMC) proliferation. Microparticles concentration dependently stimulated p42/p44 MAP kinase phosphorylation, c-fos induction, DNA synthesis, and proliferation of cultured bovine coronary artery SMC. The maximum mitogenic effects of microparticles were significantly higher than those of platelet-derived growth factor (PDGF)-BB. Microparticle-induced SMC Mitogenesis was heat sensitive, whereas the effects of PDGF were not. In addition, neutralizing anti-PDGF antibodies prevented PDGF-induced DNA synthesis but did not inhibit the effects of microparticles. In contrast to PDGF, which potently stimulated SMC migration, microparticles had only minor migratory activity. These results demonstrate a novel mechanism of SMC Mitogenesis by platelet-derived microparticles that is probably independent of PDGF.

  • Cyclooxygenase-independent inhibition of smooth muscle cell Mitogenesis by ibuprofen.
    European journal of pharmacology, 2000
    Co-Authors: Artur-aron Weber, Hakan Yildirim, Karsten Schrör
    Abstract:

    The aryl-propionic acid derivative, ketoprofen, has been shown to inhibit fibroblast growth by a cylooxygenase-dependent mechanism [Sanchez, T., Moreno, J.J., 1999. S(+) enantiomer inhibits prostaglandin production and cell growth in 3T6 fibroblast cultures. Eur. J. Pharmacol. 370, 63-67]. The present study demonstrates that ibuprofen, another aryl-propionic acid derivative, inhibited platelet-derived growth factor-BB (20 ng/ml)-induced Mitogenesis of cultured bovine coronary artery smooth muscle cells in a stereo-independent manner. In addition, pretreatment of the cells with indomethacin (3 microM) did not affect the inhibitory effects of ibuprofen enantiomers on smooth muscle cell Mitogenesis. Thus, aryl-propionic acid-type cyclooxygenase inhibitors can inhibit cell proliferation by both, cyclooxygenase-dependent and -independent ways.

  • Evidence for proteinase-activated receptor-2 (PAR-2)-mediated Mitogenesis in coronary artery smooth muscle cells.
    British journal of pharmacology, 1999
    Co-Authors: Ellen Bretschneider, Roland Kaufmann, Marina Braun, Michael Wittpoth, Erika Glusa, Götz Nowak, Karsten Schrör
    Abstract:

    This study investigates, whether in addition to the thrombin receptor (PAR-1), the proteinase-activated receptor-2 (PAR-2) is present in vascular smooth muscle cells (SMC) and mediates Mitogenesis. PAR-2 is activated by low concentrations of trypsin and the synthetic peptide SLIGRL. Stimulation of bovine coronary artery SMC by trypsin (2 nM) caused a 3 fold increase in DNLA-synthesis. A similar effect was observed with 10 nM thrombin. Trypsin-induced Mitogenesis was inhibited by soybean trypsin inhibitor, indicating that the proteolytic activity of the enzyme was required for its mitogenic effect. The specific PAR-2-activating peptide SLIGRL or the PAR1-activating peptide SFFLRN did not elicit Mitogenesis. When the SMC were exposed to SLIGRL (40 nM), a homologous desensitization of cytosolic Ca2+ mobilization was found after subsequent stimulation with trypsin (40 nM) but not thrombin (15 nM). Trypsin (2 nM) as well as SLIGRL (100 μM) activated the nuclear factor κB (NFκB) with a maximum response 2 h after stimulation of the SMC. This suggests that both agonists acted via a common receptor, PAR-2. Maximum activation of NFκB by thrombin (10 nM) was detected after 4–5 h. These data suggest that PAR-2 is present in coronary SMC and mediates a mitogenic response. Activation of NFκB via either PAR-1 or PAR-2 does not predict Mitogenesis. British Journal of Pharmacology (1999) 126, 1735–1740; doi:10.1038/sj.bjp.0702509

  • Activation of NFκB Is Essential but Not Sufficient to Stimulate Mitogenesis of Vascular Smooth Muscle Cells
    Biochemical and biophysical research communications, 1997
    Co-Authors: Ellen Bretschneider, Michael Wittpoth, Erika Glusa, Artur-aron Weber, Karsten Schrör
    Abstract:

    This study investigates the role of the transcription factor NFκB in thrombin- and thrombin receptor activating peptide (TRAP, SFLLRNPNDKYEPYF)-induced Mitogenesis of cultured bovine coronary artery smooth muscle cells (SMC). Stimulation of resting cells by thrombin (10 nM) or TRAP (10-100 μM) resulted in a comparable time-dependent activation of NFκB as detected by Western blotting and electrophoretic mobility shift assay (EMSA) of nuclear extracts. The NFκB activation was antagonized by N-acetyl-L-cysteine (20 mM) and pentoxifylline (0.5 mM). Thrombin caused a 3-4-fold increase in [3H]thymidine incorporation within 24 h which was prevented by inhibitors of NFκB activation. In contrast, TRAP did not cause any mitogenic response. These results demonstrate that activation of NFκB is an essential but not a sufficient signal for SMC Mitogenesis.

Artur-aron Weber - One of the best experts on this subject based on the ideXlab platform.

  • platelet derived microparticles stimulate coronary artery smooth muscle cell Mitogenesis by a pdgf independent mechanism
    Thrombosis Research, 2000
    Co-Authors: Artur-aron Weber, Hermann Oliver Koppen, Karsten Schrör
    Abstract:

    This study investigates the role of platelet-derived microparticles for vascular smooth muscle cell (SMC) proliferation. Microparticles concentration dependently stimulated p42/p44 MAP kinase phosphorylation, c-fos induction, DNA synthesis, and proliferation of cultured bovine coronary artery SMC. The maximum mitogenic effects of microparticles were significantly higher than those of platelet-derived growth factor (PDGF)-BB. Microparticle-induced SMC Mitogenesis was heat sensitive, whereas the effects of PDGF were not. In addition, neutralizing anti-PDGF antibodies prevented PDGF-induced DNA synthesis but did not inhibit the effects of microparticles. In contrast to PDGF, which potently stimulated SMC migration, microparticles had only minor migratory activity. These results demonstrate a novel mechanism of SMC Mitogenesis by platelet-derived microparticles that is probably independent of PDGF.

  • Cyclooxygenase-independent inhibition of smooth muscle cell Mitogenesis by ibuprofen.
    European journal of pharmacology, 2000
    Co-Authors: Artur-aron Weber, Hakan Yildirim, Karsten Schrör
    Abstract:

    The aryl-propionic acid derivative, ketoprofen, has been shown to inhibit fibroblast growth by a cylooxygenase-dependent mechanism [Sanchez, T., Moreno, J.J., 1999. S(+) enantiomer inhibits prostaglandin production and cell growth in 3T6 fibroblast cultures. Eur. J. Pharmacol. 370, 63-67]. The present study demonstrates that ibuprofen, another aryl-propionic acid derivative, inhibited platelet-derived growth factor-BB (20 ng/ml)-induced Mitogenesis of cultured bovine coronary artery smooth muscle cells in a stereo-independent manner. In addition, pretreatment of the cells with indomethacin (3 microM) did not affect the inhibitory effects of ibuprofen enantiomers on smooth muscle cell Mitogenesis. Thus, aryl-propionic acid-type cyclooxygenase inhibitors can inhibit cell proliferation by both, cyclooxygenase-dependent and -independent ways.

  • Activation of NFκB Is Essential but Not Sufficient to Stimulate Mitogenesis of Vascular Smooth Muscle Cells
    Biochemical and biophysical research communications, 1997
    Co-Authors: Ellen Bretschneider, Michael Wittpoth, Erika Glusa, Artur-aron Weber, Karsten Schrör
    Abstract:

    This study investigates the role of the transcription factor NFκB in thrombin- and thrombin receptor activating peptide (TRAP, SFLLRNPNDKYEPYF)-induced Mitogenesis of cultured bovine coronary artery smooth muscle cells (SMC). Stimulation of resting cells by thrombin (10 nM) or TRAP (10-100 μM) resulted in a comparable time-dependent activation of NFκB as detected by Western blotting and electrophoretic mobility shift assay (EMSA) of nuclear extracts. The NFκB activation was antagonized by N-acetyl-L-cysteine (20 mM) and pentoxifylline (0.5 mM). Thrombin caused a 3-4-fold increase in [3H]thymidine incorporation within 24 h which was prevented by inhibitors of NFκB activation. In contrast, TRAP did not cause any mitogenic response. These results demonstrate that activation of NFκB is an essential but not a sufficient signal for SMC Mitogenesis.

Waldemar Pruzanski - One of the best experts on this subject based on the ideXlab platform.

  • hydrolysis of lipoproteins by spla2 s enhances Mitogenesis and eicosanoid release from vascular smooth muscle cells diverse activity of spla2 s iia v and x
    Prostaglandins & Other Lipid Mediators, 2016
    Co-Authors: Waldemar Pruzanski, Julia Kopilov, A Kuksis
    Abstract:

    Mitogenesis of Vascular Smooth Muscle Cells (VSMC) plays an important role in atherogenesis. Until recently, the effect of lipid subfractions has not been clarified. Secretory phospholipases A2 (sPLA2's) hydrolyse glycerophospholipids and release pro-inflammatory lyso-lipids, oxidized and non-oxidized fatty acids and isoprostanes. They localize in the vascular wall. We hypothesized that structurally similar sPLA2's may exert different impact on VSMC. The influence of sPLA2's, IIA, V, X, HDL, LDL, and hydrolysis products was tested on Mitogenesis of VSMC, i.e., the early effect on the cell membrane phospholipids, and on PGE2 and LTB4 release, i.e., late effect of Cyclooxygenase and 5-lipooxygenase activity in VSMC. Mitogenesis was significantly enhanced by HDL and LDL, and by products of sPLA2 hydrolysis. Hydrolysis of HDL or LDL enhanced mitogenic activity in order V>X>IIA. The release of PGE2 was enhanced by group X sPLA2 and by HDL hydrolyzed by groups V and X. LDL and its hydrolysis products enhanced the release of PGE2 in order X>V>IIA. The release of LTB4 was markedly increased by LDL and HDL, and by hydrolytic products of group V and X, but not group IIA sPLA2. Our study demonstrates a diverse interaction of pro-inflammatory sPLA2's with HDL and LDL affecting both Mitogenesis and eicosanoid release from VSMC, therefore potentially enhancing their pro-atherogenic activity.

Daniel L. Altschuler - One of the best experts on this subject based on the ideXlab platform.

  • Epac, in Synergy with cAMP-dependent Protein Kinase (PKA), Is Required for cAMP-mediated Mitogenesis
    Journal of Biological Chemistry, 2007
    Co-Authors: Daniel Hochbaum, Kyoungja Hong, Guillermo Barila, Fernando Ribeiro-neto, Daniel L. Altschuler
    Abstract:

    Abstract cAMP stimulates proliferation in many cell types. For many years, cAMP-dependent protein kinase (PKA) represented the only known cAMP effector. PKA, however, does not fully mimic the action of cAMP, indicating the existence of a PKA-independent component. Since cAMP-mediated activation of the G-protein Rap1 and its phosphorylation by PKA are strictly required for the effects of cAMP on Mitogenesis, we hypothesized that the Rap1 activator Epac might represent the PKA-independent factor. Here we report that Epac acts synergistically with PKA in cAMP-mediated Mitogenesis. We have generated a new dominant negative Epac mutant that revealed that activation of Epac is required for thyroid-stimulating hormone or cAMP stimulation of DNA synthesis. We demonstrate that Epac's action on cAMP-mediated activation of Rap1 and cAMP-mediated Mitogenesis depends on the subcellular localization of Epac via its DEP domain. Disruption of the DEP-dependent subcellular targeting of Epac abolished cAMP-Epac-mediated Rap1 activation and thyroid-stimulating hormone-mediated cell proliferation, indicating that an Epac-Rap-PKA signaling unit is critical for the mitogenic action of cAMP.

  • Epac, in Synergy with cAMP-dependent Protein Kinase (PKA), Is Required for cAMP-mediated Mitogenesis
    Journal of Biological Chemistry, 2007
    Co-Authors: Daniel Hochbaum, Kyoungja Hong, Guillermo Barila, Fernando Ribeiro-neto, Daniel L. Altschuler
    Abstract:

    Abstract cAMP stimulates proliferation in many cell types. For many years, cAMP-dependent protein kinase (PKA) represented the only known cAMP effector. PKA, however, does not fully mimic the action of cAMP, indicating the existence of a PKA-independent component. Since cAMP-mediated activation of the G-protein Rap1 and its phosphorylation by PKA are strictly required for the effects of cAMP on Mitogenesis, we hypothesized that the Rap1 activator Epac might represent the PKA-independent factor. Here we report that Epac acts synergistically with PKA in cAMP-mediated Mitogenesis. We have generated a new dominant negative Epac mutant that revealed that activation of Epac is required for thyroid-stimulating hormone or cAMP stimulation of DNA synthesis. We demonstrate that Epac's action on cAMP-mediated activation of Rap1 and cAMP-mediated Mitogenesis depends on the subcellular localization of Epac via its DEP domain. Disruption of the DEP-dependent subcellular targeting of Epac abolished cAMP-Epac-mediated Rap1 activation and thyroid-stimulating hormone-mediated cell proliferation, indicating that an Epac-Rap-PKA signaling unit is critical for the mitogenic action of cAMP.

Ellen Bretschneider - One of the best experts on this subject based on the ideXlab platform.

  • Evidence for proteinase-activated receptor-2 (PAR-2)-mediated Mitogenesis in coronary artery smooth muscle cells.
    British journal of pharmacology, 1999
    Co-Authors: Ellen Bretschneider, Roland Kaufmann, Marina Braun, Michael Wittpoth, Erika Glusa, Götz Nowak, Karsten Schrör
    Abstract:

    This study investigates, whether in addition to the thrombin receptor (PAR-1), the proteinase-activated receptor-2 (PAR-2) is present in vascular smooth muscle cells (SMC) and mediates Mitogenesis. PAR-2 is activated by low concentrations of trypsin and the synthetic peptide SLIGRL. Stimulation of bovine coronary artery SMC by trypsin (2 nM) caused a 3 fold increase in DNLA-synthesis. A similar effect was observed with 10 nM thrombin. Trypsin-induced Mitogenesis was inhibited by soybean trypsin inhibitor, indicating that the proteolytic activity of the enzyme was required for its mitogenic effect. The specific PAR-2-activating peptide SLIGRL or the PAR1-activating peptide SFFLRN did not elicit Mitogenesis. When the SMC were exposed to SLIGRL (40 nM), a homologous desensitization of cytosolic Ca2+ mobilization was found after subsequent stimulation with trypsin (40 nM) but not thrombin (15 nM). Trypsin (2 nM) as well as SLIGRL (100 μM) activated the nuclear factor κB (NFκB) with a maximum response 2 h after stimulation of the SMC. This suggests that both agonists acted via a common receptor, PAR-2. Maximum activation of NFκB by thrombin (10 nM) was detected after 4–5 h. These data suggest that PAR-2 is present in coronary SMC and mediates a mitogenic response. Activation of NFκB via either PAR-1 or PAR-2 does not predict Mitogenesis. British Journal of Pharmacology (1999) 126, 1735–1740; doi:10.1038/sj.bjp.0702509

  • Activation of NFκB Is Essential but Not Sufficient to Stimulate Mitogenesis of Vascular Smooth Muscle Cells
    Biochemical and biophysical research communications, 1997
    Co-Authors: Ellen Bretschneider, Michael Wittpoth, Erika Glusa, Artur-aron Weber, Karsten Schrör
    Abstract:

    This study investigates the role of the transcription factor NFκB in thrombin- and thrombin receptor activating peptide (TRAP, SFLLRNPNDKYEPYF)-induced Mitogenesis of cultured bovine coronary artery smooth muscle cells (SMC). Stimulation of resting cells by thrombin (10 nM) or TRAP (10-100 μM) resulted in a comparable time-dependent activation of NFκB as detected by Western blotting and electrophoretic mobility shift assay (EMSA) of nuclear extracts. The NFκB activation was antagonized by N-acetyl-L-cysteine (20 mM) and pentoxifylline (0.5 mM). Thrombin caused a 3-4-fold increase in [3H]thymidine incorporation within 24 h which was prevented by inhibitors of NFκB activation. In contrast, TRAP did not cause any mitogenic response. These results demonstrate that activation of NFκB is an essential but not a sufficient signal for SMC Mitogenesis.