Oxidized LDL enhances stretch-induced smooth muscle cell proliferation through alterations in nuclear protein import

2012 ◽  
Vol 90 (12) ◽  
pp. 1559-1568 ◽  
Author(s):  
Mirna N. Chahine ◽  
Elena Dibrov ◽  
David P. Blackwood ◽  
Grant N. Pierce
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Synergistic Effect ◽  
Protein Import ◽  
Nuclear Protein ◽  
Mapk Pathway ◽  
Mechanical Stretch ◽  
Vsmc Proliferation ◽  
Nuclear Protein Import ◽  
Stimulation Of

Mechanical stress contributes to hypertension and atherosclerosis partly through the stimulation of vascular smooth muscle cell (VSMC) proliferation. Oxidized low density lipoprotein (oxLDL) is another important atherogenic factor that can increase VSMC proliferation. The purpose of this study was to investigate whether oxLDL could further enhance the proliferative action of mechanical stretch on VSMC, and to determine the mechanism responsible for this interaction. Because nuclear protein import is critical in regulating gene expression, transcription, and cell proliferation, its involvement in the mitogenic effects of oxLDL and mechanical stress was studied. OxLDL enhanced the proliferative effects of mechanical stretch on its own in rabbit aortic VSMC, and induced increases in the expression of HSP60 in an additive manner. Adenoviral-mediated overexpression of HSP60 induced increases in cell proliferation compared with uninfected VSMC. Mechanical stretch and oxLDL stimulated the rate of nuclear protein import in VSMC and increased the expression of nucleoporins. These effects were sensitive to inhibition of the MAPK pathway. We conclude that oxLDL and mechanical stretch have a synergistic effect on VSMC proliferation. This synergistic effect is induced through a stimulation of nuclear protein import via HSP60 and an activation of the MAPK pathway.

RanGAP-Mediated Nuclear Protein Import in Vascular Smooth Muscle Cells Is Augmented by Lysophosphatidylcholine

2006 ◽  
Vol 71 (2) ◽  
pp. 438-445 ◽  
Author(s):  
Randolph S. Faustino ◽  
Lyle N. W. Stronger ◽  
Melanie N. Richard ◽  
Michael P. Czubryt ◽  
David A. Ford ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Protein Import ◽  
Nuclear Protein ◽  
Muscle Cells ◽  
Nuclear Protein Import

Effects of mitogen-activated protein kinases on nuclear protein importThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 469-475 ◽  
Author(s):  
Randolph S. Faustino ◽  
Delphine C. Rousseau ◽  
Melanie N. Landry ◽  
Annette L. Kostenuk ◽  
Grant N. Pierce
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Protein Import ◽  
Nuclear Protein ◽  
Muscle Cells ◽  
Inhibitory Effects ◽  
Permeabilized Cell ◽  
A Cell ◽  
Nuclear Protein Import

ERK-2 MAP kinase activation induces inhibitory effects on nuclear protein import in vascular smooth muscle cells. The mechanism and characteristics of this effect of ERK-2 were investigated. An unusual dose-dependent effect of ERK-2 on nuclear protein import was identified. At higher concentrations (1 μg/mL) of ERK-2, nuclear protein import was stimulated, whereas lower concentrations (0.04 μg/mL) inhibited import. Intermediate concentrations exerted intermediate effects. The stimulatory and inhibitory effects at the 2 different ERK-2 concentrations were observed in both conventional, permeabilized cell assays of nuclear protein import and with in situ microinjection of smooth muscle cells. The biphasic effects of ERK-2 on import were also found for the other 2 members of the MAPK family, p38 and JNK. RanGAP was identified by structural analysis as a candidate target protein responsible for mediating the effects of ERK-2. After pretreatment with high concentrations of ERK-2, RanGAP activity was significantly increased by ~50%. In contrast, low concentrations of ERK-2 significantly attenuated RanGAP activity. These results demonstrate that all 3 members of the MAPK family can alter nuclear protein import in opposite directions depending upon the concentration of ERK-2 used. RanGAP represents the MAP kinase target whereby nuclear transport can be stimulated or inhibited.

Role of phosphoinositides in nuclear protein import in smooth muscle

2000 ◽  
Vol 151 (1) ◽  
pp. 319
Author(s):  
M.P. Czubryt ◽  
R. Jankowski ◽  
G.N. Pierce
Keyword(s):  
Smooth Muscle ◽  
Protein Import ◽  
Nuclear Protein ◽  
Nuclear Protein Import

Oxidized LDL affects smooth muscle cell growth through MAPK-mediated actions on nuclear protein import

2009 ◽  
Vol 46 (3) ◽  
pp. 431-441 ◽  
Author(s):  
Mirna N. Chahine ◽  
David P. Blackwood ◽  
Elena Dibrov ◽  
Melanie N. Richard ◽  
Grant N. Pierce
Keyword(s):  
Smooth Muscle ◽  
Cell Growth ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Protein Import ◽  
Nuclear Protein ◽  
Oxidized Ldl ◽  
Smooth Muscle Cell Growth ◽  
Nuclear Protein Import

Studying nuclear protein import in yeast

Methods ◽  
2006 ◽  
Vol 39 (4) ◽  
pp. 291-308 ◽  
Author(s):  
Deena M. Leslie ◽  
Benjamin Timney ◽  
Michael P. Rout ◽  
John D. Aitchison
Keyword(s):  
Protein Import ◽  
Nuclear Protein ◽  
Nuclear Protein Import

Cell type-specific requirement of the MAPK pathway for the growth factor action of gastrin

1999 ◽  
Vol 276 (6) ◽  
pp. G1363-G1372 ◽  
Author(s):  
Vinzenz M. Stepan ◽  
Chris J. Dickinson ◽  
John del Valle ◽  
Masashi Matsushima ◽  
Andrea Todisco
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Cell Type ◽  
Ar42j Cells ◽  
Cell Type Specific ◽  
Ar42j Cell ◽  
Stimulation Of

Gastrin (G17) has a CCKBreceptor-mediated growth-promoting effect on the AR42J rat acinar cell line that is linked to induction of both mitogen-activated protein kinase (MAPK) and c- fos gene expression. We investigated the mechanisms that regulate the growth factor action of G17 on the rat pituitary adenoma cell line GH3. Both AR42J and GH3cells displayed equal levels of CCKBreceptor expression and similar binding kinetics of125I-labeled G17. G17 stimulation of cell proliferation was identical in both cell lines. G17 stimulation of GH3cell proliferation was completely blocked by the CCKBreceptor antagonist D2 but not by the MEK inhibitor PD-98059 or the protein kinase C inhibitor GF-109203X, which completely inhibited G17 induction of AR42J cell proliferation. G17 induced a c- fos SRE-luciferase reporter gene plasmid more than fourfold in the AR42J cells, whereas it had no effect in the GH3cells. In contrast to what we observed in the AR42J cells, G17 failed to stimulate MAPK activation and Shc tyrosyl phosphorylation and association with the adapter protein Grb2. Epidermal growth factor induced the MAPK pathway in the GH3cells, demonstrating the integrity of this signaling system. G17 induced Ca2+mobilization in both the GH3and AR42J cells. The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited AR42J cell proliferation by 20%, whereas it completely blocked G17 induction of GH3cell growth. The Ca2+ionophore ionomycin stimulated GH3cell proliferation to a level similar to that observed in response to G17, but it had no effect on AR42J cell proliferation. Thus there are cell type specific differences in the requirement of the MAPK pathway for the growth factor action of G17. Whereas in the AR42J cells G17 stimulates cell growth through activation of MAPK and c- fos gene expression, in the GH3cells, G17 fails to activate MAPK, and it induces cell proliferation through Ca2+-dependent signaling pathways. Furthermore, induction of Ca2+mobilization in the AR42J cells appears not to be sufficient to sustain cell proliferation.

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