The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells. Dependence on the availability of downstream targets.

Bornfeldt, Karin E.; Campbell, Jean S.; Koyama, Hideki; Argast, Gretchen M.; Leslie, Christina C.; Raines, Elaine W.; Krebs, Edwin G.; Ross, Russell

doi:10.1172/jci119603

Cited by 148 publications

(122 citation statements)

References 60 publications

(65 reference statements)

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“…Similar ®ndings have recently been reported for dermal ®broblasts (Ihn & Tamaki, 2000). Bornfeldt et al (1997) recently demonstrated that the MAPK pathway can either mediate or inhibit cell proliferation, depending on the induction of down-stream events, most notably COX-2 meditated production of PGE 2 . Indeed, PGE 2 has been demonstrated to be a potent inhibitor of ®broblast (Mcanulty et al, 1997) and airway smooth muscle proliferation (Belvisi et al, 1998).…”

Section: Discussionsupporting

confidence: 83%

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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6JJ1 Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, acts on a variety of cells and elicits diversi®ed biological responses, suggesting potential roles in the regulation of cell survival, di erentiation and proliferation. 2 We have examined the e ect of OSM on the regulation of human lung ®broblast proliferation, collagen production and spontaneous apoptosis. The proliferative e ects of OSM (0.5 ± 100 ng ml 71 ) were assessed using a MTS assay as well as [ 3 H]-thymidine incorporation and cell counts at 24 and 48 h. Hydroxyproline was measured as an index of procollagen production by high pressure liquid chromotography (HPLC). Apoptosis was determined by annexin staining. 3 OSM enhanced the mitotic activity of lung ®broblasts in a time and dose dependent manner. Maximum proliferation of 57% above control was observed after incubation for 48 h with 2 ng ml 71 OSM (P50.05). 4 Incubation with the mitogen activated protein kinase (MAPK) kinase inhibitor, PD98059 or the tyrosine kinase inhibitor, genestein both signi®cantly reduced the mitogenic e ect of OSM (P50.05). 5 In contrast, proliferation in response to OSM was not regulated by induction of cyclo-oxygenase and subsequent prostaglandin E 2 (PGE 2 ) release or by IL-6. 6 OSM also stimulated ®broblasts to synthesize pro-collagen by a maximum of 35% above control levels after 48 h (P50.05). 7 OSM signi®cantly inhibited the spontaneous apoptosis of ®broblasts at 24 and 48 h. 8 These results provide evidence that OSM has pro-®brotic properties and suggest that it may play a role in normal lung wound repair and ®brosis.

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Section: Discussionsupporting

confidence: 83%

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Scaffidi

Mutsaers

Moodley

et al. 2002

British J Pharmacology

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“…First, in mesangial cells, glucose treatment upregulates p27 by activation of the MAP kinase pathway, leading to cell hypertrophy [49]. In addition, the MAP kinase pathway can mediate growth inhibition and proliferation in SMCs depending on the availability of downstream targets [50]. Our previous study showed that activation of the MAP kinase pathway upregulates p27 and arrests the cell cycle of epithelioid SMCs [22].…”

Section: Discussionmentioning

confidence: 99%

Phenotype-specific inhibition of the vascular smooth muscle cell cycle by high glucose treatment

2007

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Aims/hypothesis Diabetes accelerates the development of atherosclerosis, which critically involves the proliferation of vascular smooth muscle cells (SMCs). However, how high glucose treatment regulates SMC proliferation is controversial. Considering the established SMC heterogeneity, we hypothesised that glucose treatment may have distinct effects on proliferation of the various phenotypic SMCs. Materials and methods We tested this possibility using cloned spindle-shaped and epithelioid SMCs and laser scanning cytometry. Results Our results showed that glucose treatment significantly inhibited the serum-independent proliferation of epithelioid SMCs, but had no effect on the proliferation of spindle-shaped cells either with or without serum stimulation. Furthermore, glucose treatment inhibited DNA synthesis, as detected by bromodeoxyuridine (BrdU) incorporation, and increased the production of reactive oxygen species in epithelioid SMCs. The inhibition of BrdU incorporation by glucose treatment was mimicked by glucosamine and phorbol 2,13-dibutyrate, a protein kinase C (PKC) activator, and reversed by azaserine, an inhibitor of the hexosamine pathway. In addition, the inhibitory effects of glucose treatment were blocked by GF 109203X (a PKC inhibitor) and PD98058 (a MAPK/ERK kinase, MEK inhibitor), and by knockdown of MEK1 by small interfering RNA (siRNA). The addition of either GF 109203X or PD98058 also reduced the phosphorylation of MAP kinase induced by glucose treatment. Conclusions/interpretation Glucose treatment inhibits the proliferation of epithelioid, but not spindle-shaped, vascular SMCs through the activation of PKC and the MAP kinase pathway, suggesting that the effects of hyperglycaemia on vascular disease depend on the phenotype of SMCs involved.

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“…Interestingly, in human vascular smooth muscle cells, S1P is devoid of mitogenic properties, and stimulates cAMP production (20). Moreover, in these cells, PGE 2 and cAMP show antiproliferative properties (31,32), but whether S1P could provoke growth arrest was not investigated. Similarly, lysophosphatidic acid, which shares structural homology with S1P and binds to receptors of the Edg family, may also regulate cell growth positively or negatively.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

Davaille¹,

Gallois²,

Habib³

et al. 2000

Journal of Biological Chemistry

114

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Proliferation of hepatic myofibroblasts (hMF) is central for the development of fibrosis during liver injury, and factors that may limit their growth are potential antifibrotic agents. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with growth-regulating properties, either via Edg receptors or through intracellular actions. In this study, we examined the effects of S1P on the proliferation of human hMF. Human hMF expressed mRNAs for the S1P receptors Edg1, Edg3, and Edg5. These receptors were functional at nanomolar concentrations and coupled to pertussis toxin-sensitive and -insensitive G proteins, as demonstrated in guanosine 5-3-O-(thio)triphosphate binding assays. S1P potently inhibited hMF growth (IC 50 ‫؍‬ 1 M), in a pertussis toxininsensitive manner. Analysis of the mechanisms involved in growth inhibition revealed that S1P rapidly increased prostaglandin E 2 production and in turn cAMP, two growth inhibitory messengers for hMF; C 2 -ceramide and sphingosine, which inhibited hMF proliferation, did not affect cAMP levels. Production of cAMP by S1P was abolished by NS-398, a selective inhibitor of COX-2. Also, S1P potently induced COX-2 protein expression. Blocking COX-2 by NS-398 blunted the antiproliferative effect of S1P. We conclude that S1P inhibits proliferation of hMF, probably via an intracellular mechanism, through early COX-2-dependent release of prostaglandin E 2 and cAMP, and delayed COX-2 induction. Our results shed light on a novel role for S1P as a growth inhibitory mediator and point out its potential involvement in the negative regulation of liver fibrogenesis.

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The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells. Dependence on the availability of downstream targets.

Cited by 148 publications

References 60 publications

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

Phenotype-specific inhibition of the vascular smooth muscle cell cycle by high glucose treatment

Antiproliferative Properties of Sphingosine 1-Phosphate in Human Hepatic Myofibroblasts

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