OLIGODEOXYNUCLEOTIDES DIRECTED TO EARLY GROWTH-RESPONSE GENE-1 MESSENGER-RNA INHIBIT DNA-SYNTHESIS IN THE SMOOTH-MUSCLE CELL

Vascular smooth muscle cell proliferation plays a central role in the pathophysiology of cardiovascular diseases. The induction of the early growth response gene-1 (egr-1) mRNA is associated with different cell ular processes such as cell proliferation. Antisense oligodeoxynucleot ides seem to provide a promising new pharmaceutical tool for effective modification of the expression of specific genes. Hence, in the prese nt study. the effect of 15-mer antisense oligodeoxynucleotides (target ed to the initial codon region of the egr-1 mRNA) on the angiotensin I I- and platelet-derived growth factor-BB-induced growth promoting effe cts of aortic smooth muscle cells was evaluated. Angiotensin II- and p latelet-derived growth factor-BB induced egr-1 mRNA (3.4 kb) and Egr-1 protein (80 kDa) in a time- and concentration-dependent fashion. No e ffects of the sense and antisense oligodeoxynucleotides on the agonist -induced elevation of the egr-1 mRNA and on the Egr-1 protein could be demonstrated. However, they effectively inhibited the angiotensin II- and the platelet-derived growth factor-BB induced DNA synthesis. Our findings provide evidence that the oligodeoxynucleotides inhibit vascu lar smooth muscle cell growth via nonantisense mechanism(s).