Smooth muscle cell migration and proliferation are mediated by distinct phases of activation of the intracellular messenger mitogen-activated protein kinase

Nelson, Peter R.; Yamamura, Shinji; Mureebe, Leila; Itoh, Hiroyuki; Kent, K. Craig

doi:10.1016/s0741-5214(98)70298-8

Cited by 103 publications

(84 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that ERK is rapidly activated in vascular SMCs upon PDGF stimulation (28). The present study provides evidence that ERK promotes SMC proliferation, at least in part, by suppressing the expression of p27.…”

Section: Figsupporting

confidence: 73%

“…We had previously demonstrated that MAPK is essential for PDGF-induced proliferation of vascular SMCs (15,28); therefore, we wished to examine whether MAPK activity is also required for p27 down-regulation. To this end, we explored specific inhibitors of ERK, JNK, and p38, the three major types of MAPK.…”

Section: Pdgf Reduced the Level Of P27 Protein In Vascular Smcs-mentioning

confidence: 99%

See 1 more Smart Citation

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Sakakibara

Kubota

Worku

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cyclin-dependent kinase inhibitor p27, a critical determinant for cell cycle progression, is an important regulation target of mitogenic signals during arterial injury. In this study, we show in rat aortic smooth muscle cells that PDGF-BB down-regulated p27 protein and mRNA in an ERK-dependent mechanism. Inhibition of ERK, but not other subtypes of the mitogen-activated protein kinase family, prevented the reduction of p27 protein and mRNA. Conversely, direct activation of ERK via adenovirus-mediated expression of a constitutively active form of MEK led to a reduction of p27 protein and mRNA, further supporting the central role of ERK in regulation of p27 expression. Rapamycin, which potently inhibited PDGF-induced activation of p70 S6 kinase as well as proliferation of smooth muscle cells, did not alter the expression of p27. To delineate the molecular mechanism underlying the p27 down-regulation, we examined the effect of PDGF-BB on p27 promoter activity as well as mRNA stability. Stimulation with PDGF-BB significantly shortened the half-life of p27 mRNA without affecting its promoter activity. To further understand the PDGF-stimulated p27 mRNA turnover, we inserted the 5-and/or 3-untranslated regions of p27 cDNA into a non-PDGF-responsive luciferase gene. Only those chimeric genes that contained the 3-untranslated region responded to PDGF-BB with reduced expression. Moreover, inhibition of ERK completely prevented the effect of PDGF on the chimera expression. In summary, our data suggest that p27 is down-regulated by PDGF-BB in vascular smooth muscle cells through an ERK-dependent posttranscriptional mechanism.

show abstract

Section: Figsupporting

confidence: 73%

Section: Pdgf Reduced the Level Of P27 Protein In Vascular Smcs-mentioning

confidence: 99%

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Sakakibara

Kubota

Worku

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…34) Platelet-derived growth factor-induced chemotaxis and proliferation of VSMCs were regulated by Erk1/2, because Erk1/2 inhibitor PD98059 abolished platelet-derived growth factor-induced chemotaxis and proliferation of VSMCs. 35) Recently, we reported that EGF increased Ca 2+ sensitization in vascular smooth muscle and stimulated phosphorylation of Erk1/2 and MYPT1. 17) Chen et al reported that a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor inhibited stretch-induced phosphorylation of Erk1/2, JNK, and p38 MAPK.…”

Section: +mentioning

confidence: 97%

Orthovanadate-Induced Vasoconstriction of Rat Mesenteric Arteries Is Mediated by Rho Kinase-Dependent Inhibition of Myosin Light Chain Phosphatase

Ito

Matsuzaki

Sasahara

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Key words myosin light chain phosphatase; orthovanadate; mesenteric artery Vanadium forms numerous inorganic compounds (vanadyl sulfate, sodium metavanadate, sodium orthovanadate (OVA), vanadium pentoxide) and complexes with organic compounds.1) Because of its structural similarity to phosphate, vanadate possesses various biochemical and pharmacological properties, such as the ability to inhibit ATPases 2) and protein tyrosine phosphatases (PTPases), 3) epidermal growth factor (EGF)-like mitogenic activity, 4) insulin-mimetic properties, 5) anti-apoptotic activities, 6) and antitumor or carcinogenic properties. 7,8) Vanadium compounds exert contractile effects on vascular and non-vascular smooth muscle, such as the guinea pig taenia coli, trachea, and gallbladder smooth muscle.9-11) The contractile effects of vanadates have been considered to be due to inhibition of PTPase, 9,11,12) but not ATPase, 13,14) because genistein, a protein tyrosine kinase inhibitor, attenuates vanadateinduced constriction. Vanadate-induced muscle constriction was regulated by activation of Rho kinase-dependent signaling in ileal longitudinal smooth muscle in guinea pigs, resulting in increased phosphorylation of the myosin light chain (MLC). 15)These reports showed that vanadates inhibited the activity of protein tyrosine phosphatases, leading to Rho kinase-dependent constriction. Recently, we reported that OVA induced Rho kinase-dependent constriction and phosphorylation of the myosin phosphatase target subunit 1 (MYPT1) of myosin light chain phosphatase (MLCP). OVA-induced phosphorylation of MYPT1 was regulated by the EGF receptor (EGFR) and Src, because inhibitors of EGFR and Src abolished phosphorylation of MYPT1.16) Furthermore, metalloproteinase inhibitor TAPI-0 (N-(R)-(2-(hydroxyaminocarbonyl) methyl]-4-methylpentanoyl-L-naphthylalanyl-L-alanine amide) and an inhibitor of heparin/EGF binding abrogated OVA-induced aortic constriction and phosphorylation of EGFR and MYPT1.16) This finding indicated that OVA transactivated EGFR in vascular smooth muscle cells (VSMCs) derived from the rat thoracic aorta. These findings indicate that OVA can influence smooth muscle constriction through EGFR and Rho kinase-dependent inactivation of MLCP. Furthermore, we showed that EGF induced Ca 2+ sensitization in vascular smooth muscle by Rho kinasedependent inactivation of MLCP through the extracellular signal-regulated kinases 1 and 2 (Erk1/2) and Erk1/2 kinase (MEK) pathway. 17) However, it is not clear whether OVA activates MEK and Erk1/2 signaling through the EGFR. In addition, it is unknown whether OVA induces constriction and phosphorylation of MYPT1 in mesenteric arteries in rats. Therefore, in this study, we aimed to determine whether OVA-induced constriction of rat superior mesenteric arteries is mediated by Src, EGFR, mitogen-activated protein kinase (MAPK) s, and Rho kinase.

show abstract

“…The extracellular signal-regulated kinase (ERK) signaling pathway mediates VEGF-and PDGF-induced vascular remodeling (26,27). To evaluate the activation of ERK signaling in CBDL lungs, we measured expression of the active form of ERK-1, using an anti-phospho-ERK antibody.…”

Section: Activation Of Extracellular Signal-regulated Kinase Signalinmentioning

confidence: 99%

A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome

Thenappan¹,

Goel²,

Marsboom³

et al. 2011

Am J Respir Crit Care Med

171

134

View full text Add to dashboard Cite

Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. Objectives: We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion. Methods: Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n 5 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(1) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n 5 10 per group). Measurements and Main Results: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(1) macrophages (nuclear factor-kB1) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. Conclusions: HPS results from intravascular accumulation of CD68 (1) macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.Keywords: liver transplantation; arteriovenous malformations; clodronate; cirrhosis; portopulmonary hypertension Hepatopulmonary syndrome (HPS), characterized by hypoxemia and intrapulmonary shunting, occurs in 5 to 32% of patients with liver disease (1). HPS significantly increases mortality and worsens functional status and quality of life in patients with cirrhosis (2). The major pathological abnormalities in HPS include alveolar capillary dilatation and pulmonary arteriovenous malformations (3). Clinically, patients with HPS present with hypoxemia and signs of a hyperdynamic circulatory state that include low systemic vascular resistance, low pulmonary vascular resistance (PVR), and high cardiac output (CO) (1). The pathogenesis of HPS is unclear, and currently there are no effective medical therapies. Orthotopic liver transplantation is the only available treatment (1). It is noteworthy that some patients with cirr...

show abstract

Smooth muscle cell migration and proliferation are mediated by distinct phases of activation of the intracellular messenger mitogen-activated protein kinase

Abstract: MAPK activity is essential for both SMC migration and proliferation, and distinct phases of enzyme activation are required to stimulate these two discrete cellular events. Inhibition of this signaling protein may prove to be a useful method for preventing intimal hyperplasia.

Cited by 103 publications

References 21 publications

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

PDGF-BB Regulates p27 Expression through ERK-dependent RNA Turn-over inVascular Smooth MuscleCells

Orthovanadate-Induced Vasoconstriction of Rat Mesenteric Arteries Is Mediated by Rho Kinase-Dependent Inhibition of Myosin Light Chain Phosphatase

A Central Role for CD68(+) Macrophages in Hepatopulmonary Syndrome

Contact Info

Product

Resources

About