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

冠状动脉的球囊扩张是一个至关重要的 在治疗患有冠状动脉疾病的患者中的模式。 虽然初始成功率超过90%，但再狭窄发生在25至20%的患者中。 50%的患者在手术后数周或数月。 再狭窄是 由于平滑肌细胞（SMC）的激活， 中膜：球囊血管成形术损伤后， 并迁移到脑膜下，从而导致再狭窄。 我们 参与了旨在开发治疗方法的研究， 再狭窄 在这些研究中，我们使用反义 多聚脱氧核苷酸（ODNS）选择性抑制生长因子， 导致SMC增殖。 蛋白质是通过翻译 mRNA。 mRNA传达了一个真实的信息;即。它包含一个 特定蛋白质 这就是所谓的“感觉”信息。 的序列 与有义mRNA完全互补的核苷酸称为 反义，--它不编码可以翻译成 蛋白 反义序列与有义mRNA结合，从而 干扰翻译。 使用大鼠主动脉SMC，我们已经测试了针对C-myc的ODNS。 C-myc是一种 由各种有丝分裂原诱导的立即早期反应基因，以及一些 线。“证据来自于实验， 造血细胞系或转基因小鼠，表明其蛋白产物 在许多信号转导途径中起作用，包括那些 调节细胞分裂。 因此，我们推断， 使用与c-myc mRNA互补的寡脱氧核苷酸（ODN）， 反义寡核苷酸可能是SMC增殖的有效抑制剂， 也许是SMC迁移。 我们发现，反义ODNs抑制， SMC增殖和迁移均呈浓度依赖性。 这些结果表明，c-myc基因产物参与了 信号转导通路介导SMC增殖和迁移。 结果还表明反义策略的潜在作用 旨在抑制c-myc表达以预防冠状动脉疾病 再狭窄

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.