Perlecan Heparan Sulfate Is Required for the Inhibition of Smooth Muscle Cell Proliferation by All-trans-Retinoic Acid.

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). 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.

journal_name

J Cell Physiol

authors

Tran-Lundmark K,Tannenberg P,Rauch BH,Ekstrand J,Tran PK,Hedin U,Kinsella MG

doi

10.1002/jcp.24731

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

482-7

issue

2

eissn

0021-9541

issn

1097-4652

journal_volume

230

pub_type

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