Trapidil Inhibits Platelet-Derived Growth Factor–Stimulated Mitogen-Activated Protein Kinase Cascade

Hoshiya, Makiko; Awazu, Midori

doi:10.1161/01.hyp.31.2.665

Cited by 27 publications

(20 citation statements)

References 31 publications

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“…The growth inhibitory effect was completely reversed by inhibition of PKA. Trapidil is a pharmacological agent that has been shown in clinical trials to reduce post-angioplasty restenosis (7). In vitro, this agent in- FIG.…”

Section: Discussionmentioning

confidence: 99%

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cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

Klemm¹,

Watson²,

Frid³

et al. 2001

Journal of Biological Chemistry

128

136

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We hypothesized that cAMP response element-binding protein (CREB) could function as a molecular determinant of smooth muscle cell fate. In arterial sections from the systemic and pulmonary circulation, CREB content was high in proliferation-resistant medial subpopulations of smooth muscle cells and low in proliferation-prone regions. In vessels from neonatal calves exposed to chronic hypoxia, CREB content was depleted and smooth muscle cell (SMC) proliferation was accelerated. Induction of quiescence by serum deprivation in culture led to increased CREB content. Highly proliferative SMC in culture were observed to have low CREB content. Exposure to proliferative stimuli such as hypoxia or platelet-derived growth factor decreased SMC CREB content. Assessment of CREB gene transcription by nuclear run-on analysis and transcription from a CREB promoter-luciferase construct indicate that CREB levels in SMC are in part controlled at the level of transcription. Overexpression of wild type or constitutively active CREB in primary cultures of SMC arrested cell cycle progression. Additionally, expression of constitutively active CREB decreased both proliferation and chemokinesis. Consistent with these functional properties, active CREB decreased the expression of multiple cell cycle regulatory genes, as well as genes encoding growth factors, growth factor receptors, and cytokines. Our data suggest a unique mode of cellular phenotype determination at the level of the nuclear content of CREB.The vessel wall, once seen as simply a mechanical conduit for blood flow, is a complex organ whose dysfunction is responsible for the leading cause of death in the United States, cardiovascular disease. The lumen of blood vessels is lined with endothelial cells, which communicate with the underlying medial cell layer. For many years, the arterial media was considered to be made-up of a homogeneous population of smooth muscle cells (SMC) 1 arising from a common lineage. Thus the diverse activities of contraction, proliferation, migration, and extracellular matrix production were thought to reflect SMC response to either normal or pathological stimuli. Vascular remodeling is the compensatory response of the vasculature to stress or injury. Under pathological circumstances (hypoxia, mechanical injury, hyperlipidemia, and oxidative stress), SMC in the intimal and medial compartments of the arterial wall become proliferative, migratory, and produce excess matrix proteins. This switch in SMC phenotype is termed phenotypic modulation and is considered to play a key pathogenic role in atherosclerosis and pulmonary hypertension. While the stimuli for SMC activation are well known, the molecular events, which permit activation of SMC, remain poorly understood.Cyclic nucleotides (cAMP and cGMP) promote SMC quiescence in vitro and in vivo. ␤-Adrenergic stimulation of cAMP signaling is important for SMC quiescence and contractile function under normal conditions. It is believed that cAMP acts as a gate to prevent SMC mitogenic response to growth fac...

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Section: Discussionmentioning

confidence: 99%

“…Cells within the ring were trypsinized and transferred to a 24-multiwell plate for expansion. All studies will be carried out using cells at passages [1][2][3][4][5][6][7][8]. Cell cultures will be tested for mycoplasma contamination using a Gen-Probe Mycoplasma T. C. Rapid Detection System (GenProbe Inc.).…”

Section: Methodsmentioning

confidence: 99%

cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

Klemm¹,

Watson²,

Frid³

et al. 2001

Journal of Biological Chemistry

128

136

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“…[37][38][39] A variety of growth factors and peptides activate MAPK in different ways, leading either to a transient activation within 5 to 10 minutes after stimulation 19 or to a biphasic response with a sustained second peak appearing 1 or 2 hours later. 23,24 A recent study investigating the functional relevance of these kinetics reports that the early peak in PDGF-induced MAPK activation is crucial for VSMC migration, whereas the sustained second phase of MAPK activity is important for mitogenesis. 26 Potent chemoattractants such as PDGF 18 and thrombin 40 that activate MAPK in a biphasic manner 23,24 are also mitogenic for VSMC.…”

Section: Discussionmentioning

confidence: 99%

“…Since different growth factors and peptides activate MAPK either transiently (5 to 10 minutes peak) 19 or induce an additional second sustained peak in MAPK activity (5 to 10 minutes initial peak, followed by second peak 1 to 2 hours later), 23,24 we performed a time-course study of MAPK induction by TNF-␣. As shown in Figure 4, TNF-␣ (100 U/mL) induced a rapid and transient activation of MAPK that …”

Section: Tnf-␣ Transiently Activates Mapkmentioning

confidence: 99%

TNF-α–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent

Goetze¹,

Xi²,

Kawano³

et al. 1999

Hypertension

146

103

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Abstract-Migration of vascular smooth muscle cells (VSMC) is a key event in neointimal formation and atherosclerosis that may be linked to the accumulation of inflammatory cells and release of chemotactic cytokines. Tumor necrosis factor-␣ (TNF-␣) induces chemotaxis of inflammatory cells and fibroblasts, but little is known about chemotactic signaling by TNF-␣ in VSMC. The aim of this study was to investigate the role of TNF-␣ in VSMC migration and to elucidate the chemotactic signaling pathways mediating this action. TNF-␣ (50 to 400 U/mL) induced migration of cultured rat aortic VSMC in a dose-dependent manner. Because activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) is known to be required in platelet-derived growth factor-directed and angiotensin II-directed migration of these cells, we used the MAPK-inhibitor PD98059 to determine if chemotactic signaling by TNF-␣ involves the MAPK pathway as well. We found that TNF-␣-directed migration was substantially inhibited by PD98059. TNF-␣ (100 U/mL) transiently activated MAPK with a maximal induction 10 minutes after stimulation that returned to baseline levels by 2 hours after treatment. Only a single peak of increased MAPK activity was seen. PD98059 also blocked TNF-␣-stimulated MAPK activation in a concentration-dependent manner, which is consistent with its inhibition of TNF-␣-directed migration. To identify which TNF-␣ receptor is involved in TNF-␣-induced MAPK activation, antibodies against the p55 TNF-␣ receptor-1 (TNF-R1) and the p75 TNF-␣ receptor-2 (TNF-R2) were used. VSMC express both receptors, but TNF-␣-induced MAPK activation was inhibited only by the TNF-R1 antibody. The TNF-R2 antibody had no effect. Thiazolidinediones are known to inhibit TNF-␣ signaling in adipose tissue and attenuate platelet-derived growth factor-directed and angiotensin II-directed migration in VSMC. We therefore investigated the effects of the thiazolidinediones troglitazone (TRO) and rosiglitazone (

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“…Many compounds that activate adenyl cyclase (39), inhibit phosphodiesterases (50), or mimic cyclic AMP (cAMP)/cGMP (34) exert antiproliferative effects on SMC growth. Interestingly, many drugs and therapeutic agents that reduce SMC proliferation act by increasing intracellular cAMP levels (22,27,44,64). There is now substantial evidence that cAMP/PKA signaling acts as a molecular gate to block MAPK-induced proliferation in response to mitogens such as PDGF (5,23,30,44).…”

mentioning

confidence: 99%

Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells

Garat

Fankell²,

Erickson³

et al. 2006

Molecular and Cellular Biology

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. These results indicate that in addition to direct phosphorylation, proteolysis and intracellular localization are key mechanisms regulating CREB content and activity in SMCs.Pulmonary hypertension (PH) and related vascular pathologies are characterized by changes in the structure of the arterial wall. These changes are largely due to the proliferation and hypertrophy of smooth muscle cells (SMCs) and increased SMC deposition of extracellular matrix in the vessel wall. The proliferation and hypertrophy of SMCs are stimulated by growth factors and proinflammatory agents such as plateletderived growth factor BB (PDGF-BB), insulin-like growth factors I and II, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, endothelin-1, and thrombospondin-1, which are produced by endothelial cells, SMCs, fibroblasts, and platelets in response to vascular injury (6,11,14,15,46,59). Binding of these growth factors to their respective receptors activates associated tyrosine kinases, G proteins, and C-type phospholipases. Activation of receptor tyrosine kinases stimulates mitogen-activated protein kinase (MAPK) signaling cascades, with PDGF-BB stimulation of extracellular signal-regulated kinase 1 (ERK1)/ERK2 being a widely studied example (23, 44). G protein-coupled receptors may regulate numerous signaling pathways, with recent studies implicating RhoA/Rho kinase signaling in SMC growth and migration (52). These signaling pathways modulate the activity of downstream effectors of growth such as cyclin-dependent kinases (42) and immediate-early genes (49).These growth-promoting pathways are normally restrained in healthy arteries by endogenous mediators such as prostacyclin and NO. These agents exert antiproliferative effects on SMCs largely by increasing intracellular levels of cyclic nucleotides (53, 54), which stimulate the activity of protein kinase A (PKA) and GMP-stimulated protein kinase. Many compounds that activate adenyl cyclase (39), inhibit phosphodiesterases (50), or mimic cyclic AMP (cAMP)/cGMP (34) exert antiproliferative effects on SMC growth. Interestingly, many drugs and therapeutic agents that reduce SMC proliferation act by increasing intracellular cAMP levels (22,27,44,64). There is now substantial evidence that cAMP/PKA signaling acts as a molecular gate to block MAPK-induced proliferation in response to mitogens such as PDGF (5,23,30,44). Activation of cAMP signaling in SMCs decreases the expression of cyclin D1 and Cdk2 (60), increases the expression of antiproliferative molecules such as p53 and p21 (25), and increases overall sensitivity to antiproliferative stimuli.Given the potent proliferation-suppressing action of cAMP on SMCs, we hypothesized that the transcription factor CREB,

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Trapidil Inhibits Platelet-Derived Growth Factor–Stimulated Mitogen-Activated Protein Kinase Cascade

Cited by 27 publications

References 31 publications

cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

cAMP Response Element-binding Protein Content Is a Molecular Determinant of Smooth Muscle Cell Proliferation and Migration

TNF-α–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent

Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells

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