COP-1, a member of the CCN family, is a heparin-induced growth arrest specific gene in vascular smooth muscle cells

Vascular smooth muscle cell (VSMC) hyperplasia is responsible for the failu re of 15-30% of vascular surgical procedures such as coronary artery bypass grafts and angioplasties. We and others have shown that heparin suppresses VSMC proliferation in vivo and in cell culture. We hypothesize that hepari n inhibits VSMC proliferation by binding to cell surface receptors, resulti ng in selective modulation of mitogenic signal transduction pathways and al tered transcription of a specific subset of growth regulatory genes. To tes t this idea, we used subtractive hybridization to identify differentially e xpressed mRNAs in heparin-treated and untreated VSMC. We identified a hepar in induced mRNA identical to Cop-1, a member of the CCN family of proteins which are secreted, cysteine-rich modular proteins involved in growth regul ation and migration. Cop-1 from smooth muscle cells appears to have a diffe rent expression pattern and possibly different functions than Cop-1 from ot her cells. Cop-1 mRNA is expressed at high levels in quiescent VSMC and at low levels in proliferating VSMC, an expression pattern highly characterist ic of growth arrest specific genes. Cop-1 mRNA is expressed at high levels in heparin treated VSMC and COP-1 protein is secreted into culture medium. In tissues, Cop-1 expression is observed in the uninjured rat aorta suggest ing a possible role for Cop-1 in vivo. We found PDGF, but not EGF, inhibits the expression of Cop-1 in VSMC. Neither TGF-beta nor interferon-beta, two inhibitors of VSMC proliferation, were able to induce Cop-1 expression. In addition, heparin does not induce Cop-1 mRNA. in endothelial cells and VSM C resistant to the antiproliferative effect of heparin. Conditioned medium from cells over-expressing COP-1 protein inhibits VSMC proliferation in cul ture. Together, our data indicate that COP-1 may play a role in the antipro liferative mechanism of action of heparin. (C) 2001 Wiley-Liss, Inc.