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Perlecan heparan sulfate is required for the inhibition of smooth muscle cell proliferation by all-trans-retinoic acid

Tran-Lundmark, Karin LU ; Tannenberg, Philip ; Rauch, Bernhard H. ; Ekstrand, Johan ; Tran, Phan Kiet LU ; Hedin, Ulf and Kinsella, Michael G. (2015) In Journal of Cellular Physiology 230(2). p.482-487
Abstract

Smooth muscle cell (SMC) proliferation is a key process in stabilization of atherosclerotic plaques, and during restenosis after interventions. A clearer understanding of SMC growth regulation is therefore needed to design specific anti-proliferative therapies. Retinoic acid has been shown to inhibit proliferation of SMCs both in vitro and in vivo and to affect the expression of extracellular matrix molecules. To explore the mechanisms behind the growth inhibitory activity of retinoic acid, we hypothesized that retinoids may induce the expression of perlecan, a large heparan sulfate proteoglycan with anti-proliferative properties. Perlecan expression and accumulation was induced in murine SMC cultures by all-trans-retinoic acid (AtRA).... (More)

Smooth muscle cell (SMC) proliferation is a key process in stabilization of atherosclerotic plaques, and during restenosis after interventions. A clearer understanding of SMC growth regulation is therefore needed to design specific anti-proliferative therapies. Retinoic acid has been shown to inhibit proliferation of SMCs both in vitro and in vivo and to affect the expression of extracellular matrix molecules. To explore the mechanisms behind the growth inhibitory activity of retinoic acid, we hypothesized that retinoids may induce the expression of perlecan, a large heparan sulfate proteoglycan with anti-proliferative properties. Perlecan expression and accumulation was induced in murine SMC cultures by all-trans-retinoic acid (AtRA). Moreover, the growth inhibitory effect of AtRA on wild-type cells was greatly diminished in SMCs from transgenic mice expressing heparan sulfate-deficient perlecan, indicating that the inhibition is perlecan heparan sulfate-dependent. In addition, AtRA influenced activation and phosphorylation of PTEN and Akt differently in wild-type and mutant SMCs, consistent with previous studies of perlecan-dependent SMC growth inhibition. We demonstrate that AtRA regulates perlecan expression in SMCs and that the inhibition of SMC proliferation by AtRA is, at least in part, secondary to an increased expression of perlecan and dependent upon its heparan sulfate-chains.

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author
; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Journal of Cellular Physiology
volume
230
issue
2
pages
482 - 487
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:84911192058
  • pmid:25078760
ISSN
0021-9541
DOI
10.1002/jcp.24731
language
English
LU publication?
no
id
9c9f1398-3e87-45b7-925a-7035b1d1e9a8
date added to LUP
2019-07-01 22:14:31
date last changed
2024-04-30 17:03:20
@article{9c9f1398-3e87-45b7-925a-7035b1d1e9a8,
  abstract     = {{<p>Smooth muscle cell (SMC) proliferation is a key process in stabilization of atherosclerotic plaques, and during restenosis after interventions. A clearer understanding of SMC growth regulation is therefore needed to design specific anti-proliferative therapies. Retinoic acid has been shown to inhibit proliferation of SMCs both in vitro and in vivo and to affect the expression of extracellular matrix molecules. To explore the mechanisms behind the growth inhibitory activity of retinoic acid, we hypothesized that retinoids may induce the expression of perlecan, a large heparan sulfate proteoglycan with anti-proliferative properties. Perlecan expression and accumulation was induced in murine SMC cultures by all-trans-retinoic acid (AtRA). Moreover, the growth inhibitory effect of AtRA on wild-type cells was greatly diminished in SMCs from transgenic mice expressing heparan sulfate-deficient perlecan, indicating that the inhibition is perlecan heparan sulfate-dependent. In addition, AtRA influenced activation and phosphorylation of PTEN and Akt differently in wild-type and mutant SMCs, consistent with previous studies of perlecan-dependent SMC growth inhibition. We demonstrate that AtRA regulates perlecan expression in SMCs and that the inhibition of SMC proliferation by AtRA is, at least in part, secondary to an increased expression of perlecan and dependent upon its heparan sulfate-chains.</p>}},
  author       = {{Tran-Lundmark, Karin and Tannenberg, Philip and Rauch, Bernhard H. and Ekstrand, Johan and Tran, Phan Kiet and Hedin, Ulf and Kinsella, Michael G.}},
  issn         = {{0021-9541}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{482--487}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Cellular Physiology}},
  title        = {{Perlecan heparan sulfate is required for the inhibition of smooth muscle cell proliferation by all-trans-retinoic acid}},
  url          = {{http://dx.doi.org/10.1002/jcp.24731}},
  doi          = {{10.1002/jcp.24731}},
  volume       = {{230}},
  year         = {{2015}},
}