ANTISENSE TARGETED TO C-MYC MRNA INHIBITS SMOOTH MUSCLE CELL PROLIFERATION

球囊扩张冠状动脉是非常重要的

Balloon dilatation of the coronary arteries is a critically important modality in treating patients suffering from coronary artery disease. Although the initial success rate is over 90%, restenosis occurs in 25 to 50% of patients weeks or months following the procedure. Restenosis is due to activation of smooth muscle cells (SMC) that normally reside in the media: after they are injured by balloon angioplasty they proliferate and migrate to the subentema, such that they can lead to restenosis. We are involved in research aimed at developing therapy to prevent restenosis. In these studies we are using antisense olygodeoxynucleotides (ODNS) to selectively inhibit growth factors that cause SMC proliferation. Proteins are synthesized by translation of mRNA. The mRNA conveys a real message; ie. it contains the code for a specific protein. This is called the "sense" message. The sequence of nucleotides that are the exact compliment of the sense mRNA is called antisense,--it does not encode a message that can be translated into a protein. The antisense sequence binds to the sense mRNA, thereby interfering with translation. Using rat aortic SMC, we have tested ODNS targeted to C-myc. C-myc is an immediate early response gene induced by various mitogens, and several lines of .'evidence derived from experiments using transformed or hematopoietic cell lines, or transgenic mice, suggest its protein product plays a role in numerous signaling transduction pathways, including those modulating cell division. We therefore reasoned that a strategy employing oligodeoxynucleotides (ODNs) complementary to c-myc mRNA (antisense ODNs) might be potent inhibitors of SMC proliferation, and perhaps of SMC migration. We found that antisense ODNs inhibited, in a concentration-dependent manner, both SMC proliferation and SMC migration. These results indicate that the c-myc gene product is involved in the signal transduction pathways mediating SMC proliferation and migration. The results also suggest a potential role of antisense strategies designed to inhibit c-myc expression for the prevention of coronary restenosis.