Downregulation of the ERK 1 and 2 mitogen activated protein kinases using antisense oligonucleotides inhibits proliferation of porcine vascular smooth muscle cells

The current model of the arterial response to injury suggests that proliferation of vascular smooth muscle cells is a central event. Mitogen activated protein kinases are part of the final common pathway of intracellular signalling involved in cell division and thus constitute an attractive target in attempting to inhibit this proliferation. We hypothesised that antisense oligonucleotides to mitogen activated protein kinase would inhibit serum induced smooth muscle cell proliferation by downregulating the protein. Porcine vascular smooth muscle cells were cultured and an antisense oligonucleotide sequence against the ERK family of mitogen activated protein kinases (AMK1) was introduced by liposomal transfection. Sense oligonucleotides and a random sequence were used as controls. Proliferation was inhibited by AMK1 versus the sense controls, as assessed by tritiated thymidine incorporation (P < 0.01). Immunoblots revealed downregulation of the target protein by AMK1 by 63% versus the sense control (P < 0.05). In conclusion, antisense oligonucleotides specifically inhibited proliferation and downregulated the target protein. This is consistent with a central role for mitogen activated protein kinases in Vascular smooth muscle cell proliferation in the porcine model. In addition, the data suggest a possible role for antisense oligonucleotides in the modulation of the arterial injury response. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.