cGMP-Elevating Agents Suppress Proliferation of Vascular Smooth Muscle Cells by Inhibiting the Activation of Epidermal Growth Factor Signaling Pathway

Sun, Yu; Hung, Li-Man; Lin, Chih‐Ming

doi:10.1161/01.cir.95.5.1269

Cited by 190 publications

(142 citation statements)

References 30 publications

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“…Yu et al (12) reported that cGMPelevating agents suppress proliferation of VSMC, presumably through the activation of PKG and the phosphorylation of Raf-1. The major evidence presented that suggested the involvement of PKG was the sensitivity of the effects to the purported PKG inhibitor, KT 5823.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of ERK Activation by Selective Kinase InhibitorsPrevious studies have examined the effects of protein kinase inhibitors on MAP kinase activation in various cell types (12,57). Although it is evident that compounds previously believed to be selective for inhibiting PKA and PKG are not selective when used as described in intact cells (58,59), we were interested in determining whether or not there were any effects of these compounds on MAP kinase activity in the PKG-deficient and PKG-expressing adult RASMC.…”

Section: Effects Of 8-br-camp On Erk Activity In Rasmc-it Is Wellmentioning

confidence: 99%

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Activation of Mitogen-activated Protein Kinase Pathways by Cyclic GMP and Cyclic GMP-dependent Protein Kinase in Contractile Vascular Smooth Muscle Cells

Komalavilas

Shah

et al. 1999

Journal of Biological Chemistry

136

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Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo.The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal-regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC. Vascular smooth muscle cell (VSMC)1 proliferation and migration are associated with several vascular diseases such as atherosclerosis and restenosis following vascular injury (1-5). VSMC from several species when cultured in vitro undergo a change in phenotype from a contractile state to a synthetic state similar to the changes that occur with VSMC in vivo in response to vascular injury (6 -8). Several lines of evidence suggest that nitric oxide (NO) inhibits VSMC proliferation (9 -13), suggesting that signal transduction pathways regulated by NO may be important in VSMC phenotypic modulation. NO stimulates the production of cyclic GMP (14), which, in turn, regulates several functions of VSMC such as smooth muscle relaxation (15). The major receptor protein for cGMP in VSMC is cGMP-dependent protein kinase (PKG), a serine/ threonine kinase that catalyzes the phosphorylation of important proteins that regulate intracellular Ca 2ϩ levels and relaxation of vascular smooth muscle (16). Our laboratory has recently demonstrated that PKG also plays a major role in the regulation of the phenotype and morphology of VSMC (17, 18).The expression of PKG is highly variable in VSMC. When adult rat aortic SMC are subcultured in vitro, PKG expression is reduced to nearly un...

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Section: Discussionmentioning

confidence: 99%

Section: Effects Of 8-br-camp On Erk Activity In Rasmc-it Is Wellmentioning

confidence: 99%

Activation of Mitogen-activated Protein Kinase Pathways by Cyclic GMP and Cyclic GMP-dependent Protein Kinase in Contractile Vascular Smooth Muscle Cells

Komalavilas

Shah

et al. 1999

Journal of Biological Chemistry

136

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“…To examine the potential role of cGMP-dependent protein kinase (cGPK) in the regulation of PAI-1 expression, cells were treated with KT5823, an inhibitor of cGPK previously shown to interfere with a variety of other actions of natriuretic factors and nitric oxide. 27,[43][44][45] Pretreatment of cells with 10 mol/L KT5823 for 10 minutes did not significantly alter Ang II stimulation or ANF suppression of PAI-1 mRNA levels ( Figure 6, bottom right). Thus, whereas cGMP appears to play an important role in the suppression of PAI-1 expression by natriuretic factors and nitric oxide, this effect of cGMP does not appear to require cGPK activity.…”

Section: Anf and Cnp Primarily Signal Via Natriuretic Peptide Receptomentioning

confidence: 93%

Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells

Bouchie

Hansen

Feener

1998

ATVB

105

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Abstract-Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been reported in atherosclerotic and balloon-injured vessels. Little is known regarding the factors and mechanisms that may negatively regulate PAI-1 expression. In this report, the effect of cGMP-coupled vasoactive hormones, including natriuretic factors and nitric oxide, on the regulation of PAI-1 expression in vascular smooth muscle cells was examined. Atrial natriuretic factor 1-28 (ANF) and C-type natriuretic factor-22 (CNP) reduced angiotensin II (Ang II)-and platelet-derived growth factor-stimulated PAI-1 mRNA expression in rat aortic smooth muscle cells by 50% to 70%, with corresponding reductions in PAI-1 protein release. Treatment of human aortic smooth muscle cells with CNP similarly inhibited both platelet-derived growth factor-induced PAI-1 mRNA expression and PAI-1 protein release by 50%. Dose-response studies revealed that the inhibitory effects of CNP and ANF on PAI-1 expression were concentration dependent, with IC 50 s of Ϸ1 nmol/L for both natriuretic peptides. Ang II-stimulated PAI-1 expression was also inhibited by the nitric oxide donor S-nitroso-N-acetylpenicillamine.

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“…Although the MAPK pathway is a recognized signal transducer for neurotrophins, only recently have both ANP type -A and -C (CNP) and cGMP been shown to utilize this pathway. Both inhibition 73,74 and activation [75][76][77][78] of the MAPK pathway are seen in response to these molecules. The mechanisms underlying these responses are not fully understood.…”

confidence: 99%

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Simpson

Moon²,

Kleman

et al. 2007

Cell Cycle

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ACKnowlEdGEMEntSWe thank Amy Palmer for helpful discussions and reading of the manuscript, and Susan McTeer for manuscript preparation. This work was supported by grants NIDCD RO3 DC005704 to P.J.S., NIDCD RO1 DC02979 and NINDS RO1 NS39657 to G.V.R. AbStRACtNeuronal stem cell expansion and differentiation is a process involving stages of proliferation and maturation governed by the sequential and combinatorial exposure of cells to extrinsic factors. The olfactory epithelium is an excellent model to investigate regulation of this process, as it undergoes neuronal replacement post-natally. We have shown that the neurotrophins NGF and BDNF sequentially promote proliferation of developing olfactory sensory neuronal precursors, although their kinetics of proliferation and cell fate outcomes differ. Interestingly, CNP inhibits this neurotrophin-induced proliferation and promotes the maturation of these precursors to their next developmental stage. Here, we investigate the mechanisms behind these actions. Both NGF and BDNF increase the expression of cyclin D1 and cyclin-dependent kinase 4 (cdk4), with temporal expression patterns that parallel the proliferation kinetics of their cellular targets. The timing of cyclin D1 expression reflects differences in the need for transcription and translation in early and late stage precursors. CNP inhibits neurotrophin-induced cyclin D1 expression, and induces the expression of different profiles of inhibitory cell cycle proteins, which are neurotrophin-specific and correlate with the attainment of different maturational cell fates. Inhibition of protein degradation reverses the effects of neurotrophins and CNP on cyclin D1 and inhibitor expression levels, respectively. These results suggest a model for cell cycle regulation that involves the simultaneous expression of progressive and inhibitory cell cycle regulatory proteins in response to both proliferation and differentiation agents, followed by selective degradation of these proteins, providing a mechanism for rapid and exquisite control of the cell cycle.

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cGMP-Elevating Agents Suppress Proliferation of Vascular Smooth Muscle Cells by Inhibiting the Activation of Epidermal Growth Factor Signaling Pathway

Abstract: These results demonstrate that cGMP-elevating agents inhibit [3H]thymidine incorporation and thus the growth of VSMC, and this inhibition appears to attenuate EGF-activated signal transduction pathway by preventing Ras-dependent activation of Raf-1.

Cited by 190 publications

References 30 publications

Activation of Mitogen-activated Protein Kinase Pathways by Cyclic GMP and Cyclic GMP-dependent Protein Kinase in Contractile Vascular Smooth Muscle Cells

Activation of Mitogen-activated Protein Kinase Pathways by Cyclic GMP and Cyclic GMP-dependent Protein Kinase in Contractile Vascular Smooth Muscle Cells

Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

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