Heparin inhibits c-fos and c-myc mRNA expression in vascular smooth muscle cells.

Abstract

Heparin is a potent inhibitor of vascular smooth muscle cell (VSMC) growth. In this paper we show that heparin suppressed the induction of c-fos and c-myc mRNA in rat and calf VSMC. This effect of heparin is closely associated with its growth-inhibitory activity, as shown by isolating and characterizing a strain of rat VSMC that was resistant to heparin's antiproliferative effect; heparin did not suppress c-fos mRNA induction in these cells. Moreover, neither a nonantiproliferative heparin fragment or other glycosaminoglycans that lack growth-inhibitory activity repressed c-fos or c-myc mRNA levels. The effect of heparin on c-fos mRNA induction was selective for specific mitogens, as heparin inhibited c-fos mRNA induction in phorbol 12-myristate 13-acetate (TPA) stimulated but not epidermal growth factor (EGF) stimulated VSMC. The effect of heparin on gene expression is independent of ongoing protein synthesis, and inhibition of c-fos mRNA is at the transcriptional level. These results suggest that heparin may selectively inhibit a protein kinase C-dependent pathway for protooncogene induction and that this may be one mechanism used by heparin to inhibit cell proliferation.

Adenine nucleotides stimulate migration in wounded cultures of kidney epithelial cells.

“…Heparin modulates the action of specific growth factors, expression ofgrowth-regulatory genes, and production ofECM components (34)(35)(36)(37), and stimulates migration ofbovine capillary endothelial cells in vitro (38). The effect of heparin on migration of BSC-1 cells was ascertained by adding specified concentrations to wounded cultures and assaying migration 1 d later.…”

Antiproliferative and c‐myc mRNA suppressive effects of tranilast on newborn human vascular smooth muscle cells in culture

“…Upon ligand binding, the intrinsic kinase activities of these receptors are increased, thereby initiating a cascade of events such as elevated phospholipid metabolism and Ca2+-influx, which lead to subsequent DNA synthesis (Ronnstrand et al, 1992;Pazin et al, 1992 (Dean et al, 1986;Bennett et al, 1994). For example, it is known that c-myc is down-regulated in response to mitogen withdrawal or to the action of antiproliferative cytokine interferon-y (IFN-y) or of growth inhibitors like heparin, cyclic AMP, and cyclic GMP analogues (Pukac et al, 1990;Bennett et al, 1994). Also, antisense oligodeoxynucleotides targeting c-myc mRNA were shown to inhibit VSMC proliferation as well as their migration (Biro et al, 1993;Bennett et al, 1994).…”

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

“…Numerous reports have identified VSMC responses to heparin. These responses include decreases in cell proliferation (18,19), ERK pathway activity (19 -21), and activation of specific transcription factors (21)(22)(23). Heparin binding results in increased levels of DUSP1 protein that are required for decreases in ERK activity (24).…”