title: 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.
authors: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors: Karin
authors: K
authors: Tran-Lundmark
authors: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors: Philip
authors: P
authors: Tannenberg
authors: Institute of Pharmacology, Center of Drug Absorption and Transport, Ernst-Moritz-Arndt University, Greifswald, Germany.
authors: Bernhard H
authors: BH
authors: Rauch
authors: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors: Johan
authors: J
authors: Ekstrand
authors: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors: Phan-Kiet
authors: PK
authors: Tran
authors: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors: Ulf
authors: U
authors: Hedin
authors: Benaroya Research Institute at Virginia Mason, Seattle, Washington.
authors: Michael G
authors: MG
authors: Kinsella
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D014212:Tretinoin; C071927:perlecan