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 prolifer ation of vascular smooth muscle cells is a central event. Mitogen activated protein kinases are part of the final common pathway of intracellular sign alling involved in cell division and thus constitute an attractive target i n attempting to inhibit this proliferation. We hypothesised that antisense oligonucleotides to mitogen activated protein kinase would inhibit serum in duced smooth muscle cell proliferation by downregulating the protein. Porci ne vascular smooth muscle cells were cultured and an antisense oligonucleot ide sequence against the ERK family of mitogen activated protein kinases (A MK1) 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 incorporatio n (P < 0.01). Immunoblots revealed downregulation of the target protein by AMK1 by 63% versus the sense control (P < 0.05). In conclusion, antisense o ligonucleotides specifically inhibited proliferation and downregulated the target protein. This is consistent with a central role for mitogen activate d protein kinases in Vascular smooth muscle cell proliferation in the porci ne model. In addition, the data suggest a possible role for antisense oligo nucleotides in the modulation of the arterial injury response. (C) 2001 Els evier Science Ireland Ltd. All rights reserved.