Inhibition of rat smooth muscle cell adhesion and proliferation by non-anticoagulant heparins.
Heparin is a well established growth inhibitor of arterial smooth muscle cells (SMCs) both in animal models and in vitro. Even though the cellular mechanisms involved in the anti-proliferative properties of heparin are being resolved, the structural requirements for the biological effects of heparin are not known in detail. Here, we have studied the effect of chemically modified heparins of different molecular weights and anticoagulant activities on proliferation and adhesion of rat aortic SMCs in vitro. The effects of native heparin (NH) and chemically modified heparins were examined after stimulation with fetal calf serum (FCS), platelet-derived growth factor BB (PDGF BB), basic fibroblast growth factor (bFGF), and heparin-binding epidermal growth factor (hbEGF) with respect to DNA synthesis and expression of phosphorylated and activated mitogen-activated protein kinase (pERK1 and 2). In a similar manner as NH, the modified heparins were capable of inhibiting activation of ERK1 and 2 and DNA synthesis induced by FCS and hbEGF whereas the modified heparins potentiated the mitogenic effect of bFGF and no compound affected PDGF BB-induced ERK activity and SMC growth. In contrast, cell adhesion to fibronectin was inhibited by NH and modified heparins in a size-dependent manner with the lowest effect by the smallest compound. The results show that heparins with varying anticoagulant activities and molecular weights but with similar sulfate content can retain anti-proliferative properties while the effect on some other biological processes such as cell adhesion is lost. Possibly, such chemical alterations may yield useful substances for the prevention of SMC proliferation after arterial injury.
Kazi
Monsur
M
Division of Vascular Surgery, Department of Surgical Sciences, Karolinska Hospital, Stockholm, Sweden.
Lundmark
Karin
K
Religa
Piotr
P
Gouda
Ibrahim
I
Larm
Olle
O
Ray
Asim
A
Swedenborg
Jesper
J
Hedin
Ulf
U
D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006493:Heparin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000925:Anticoagulants; D005353:Fibronectins; D006131:Growth Inhibitors; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin; D004247:DNA; D020928:Mitogen-Activated Protein Kinases