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

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Abstract
Vascular smooth muscle cell (VSMC) hyperplasia is responsible for the failure 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 heparin inhibits VSMC proliferation by binding to cell surface receptors, resulting in selective modulation of mitogenic signal transduction pathways and altered transcription of a specific subset of growth regulatory genes. To test this idea, we used subtractive hybridization to identify differentially expressed mRNAs in heparin-treated and untreated VSMC. We identified a heparin induced mRNA identical to Cop-1, a member of the CCN family of proteins which are secreted, cysteine-rich modular proteins involved in growth regulation and migration. Cop-1 from smooth muscle cells appears to have a different expression pattern and possibly different functions than Cop-1 from other cells. Cop-1 mRNA is expressed at high levels in quiescent VSMC and at low levels in proliferating VSMC, an expression pattern highly characteristic 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 suggesting a possible role for Cop-1 in vivo. We found PDGF, but not EGF, inhibits the expression of Cop-1 in VSMC. Neither TGF-β nor interferon-β, 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 VSMC resistant to the antiproliferative effect of heparin. Conditioned medium from cells over-expressing COP-1 protein inhibits VSMC proliferation in culture. Together, our data indicate that COP-1 may play a role in the antiproliferative mechanism of action of heparin.

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