Downregulation of c-myc expression by antisense oligonucleotides inhibits proliferation of human smooth muscle cells.
Downregulation of c-myc expression by antisense oligonucleotides inhibits proliferation of human smooth muscle cells.
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反义寡核苷酸下调 c-myc 表达可抑制人平滑肌细胞的增殖。
DOI：
10.1161/01.cir.88.3.1190
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发表时间：
1993
期刊：
影响因子：
37.8
通讯作者：
Zalewski,A
中科院分区：
文献类型：
--
作者：
Shi,Y;Hutchinson,HG;Hall,DJ;Zalewski,A
BACKGROUNDProliferation of smooth muscle cells (SMCs) plays an important role in vascular pathobiology, being involved in the development of coronary restenosis and atherosclerosis. The activation of nuclear proto-oncogenes appears to be a final common pathway onto which various mitogenic signals coverage. Accordingly, we attempted to determine whether the activation of the c-myc nuclear proto-oncogene is essential for human SMC proliferation and explored the possibility of inhibiting their growth using antisense oligonucleotides directed against c-myc messenger RNA (mRNA).METHODS AND RESULTSProliferation of human SMCs was associated with an increase in c-myc mRNA expression after growth stimulation. Using 15-mer phosphorothioate oligonucleotides (oligomers), we tested their growth-inhibitory effect in SMCs in vitro. Antisense oligomers directed against the translation initiation region of the human c-myc gene exhibited a significant antiproliferative effect, whereas sense and mismatched oligomers did not inhibit the growth. The growth-inhibitory effect of c-myc antisense oligomers was dose dependent and preventable by an excess of sense oligomers. Furthermore, growth inhibition of SMCs treated with c-myc antisense oligomers was associated with a marked decrease in the c-myc mRNA level. Phosphorothioate oligomers remained stable in medium containing 20% serum and were detectable in SMCs as early as 1 hour after cell exposure. Intact oligomers rapidly accumulated intracellularly and persisted within human SMCs for at least 16 hours.CONCLUSIONSc-myc antisense oligomers reduced c-myc expression and produced a significant growth inhibition of human SMCs, indicating an important role of c-myc gene activation in the process of SMC proliferation. Furthermore, extracellular stability and rapid cellular uptake provide the basis for future studies assessing the therapeutic role of the c-myc antisense approach in reducing SMC proliferation in the process of vascular restenosis.
