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(Circulation Research. 2008;103:43.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis

Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation

Karin Tran-Lundmark, Phan-Kiet Tran, Gabrielle Paulsson-Berne, Vincent Fridén, Raija Soininen, Karl Tryggvason, Thomas N. Wight, Michael G. Kinsella, Jan Borén^*, Ulf Hedin^*

From the Department of Molecular Medicine and Surgery (K.T.-L., P.-K.T., U.H.), Karolinska Institutet, Stockholm, Sweden; the Center for Molecular Medicine (G.P.-B.), Karolinska Institutet, Stockholm, Sweden; Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine (V.F., J.B.), Göteborg University, Gothenburg, Sweden; the Department of Medical Biochemistry and Molecular Biology (R.S.), Biocenter Oulu, University of Oulu, Finland; the Department of Medical Biochemistry and Biophysics (K.T.), Karolinska Institutet, Stockholm, Sweden; and the Benaroya Research Institute at Virginia Mason (T.N.W., M.G.K.), Seattle, Wash.

Correspondence to Karin Tran-Lundmark, MD, Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, SE-17176 Stockholm, Sweden. E-mail karin.tran.lundmark{at}ki.se

Heparan sulfate (HS) has been proposed to be antiatherogenic through inhibition of lipoprotein retention, inflammation, and smooth muscle cell proliferation. Perlecan is the predominant HS proteoglycan in the artery wall. Here, we investigated the role of perlecan HS chains using apoE null (ApoE0) mice that were cross-bred with mice expressing HS-deficient perlecan (Hspg2^3/3). Morphometry of cross-sections from aortic roots and en face preparations of whole aortas revealed a significant decrease in lesion formation in ApoE0/Hspg2^3/3 mice at both 15 and 33 weeks. In vitro, binding of labeled mouse triglyceride-rich lipoproteins and human LDL to total extracellular matrix, as well as to purified proteoglycans, prepared from ApoE0/Hspg2^3/3 smooth muscle cells was reduced. In vivo, at 20 minutes influx of human ¹²⁵I-LDL or mouse triglyceride-rich lipoproteins into the aortic wall was increased in ApoE0/Hspg2^3/3 mice compared to ApoE0 mice. However, at 72 hours accumulation of ¹²⁵I-LDL was similar in ApoE0/Hspg2^3/3 and ApoE0 mice. Immunohistochemistry of lesions from ApoE0/Hspg2^3/3 mice showed decreased staining for apoB and increased smooth muscle -actin content, whereas accumulation of CD68-positive inflammatory cells was unchanged. We conclude that the perlecan HS chains are proatherogenic in mice, possibly through increased lipoprotein retention, altered vascular permeability, or other mechanisms. The ability of HS to inhibit smooth muscle cell growth may also influence development as well as instability of lesions.

Key Words: atherosclerosis • lipoproteins • perlecan • heparan sulfate • smooth muscle cells