Shi Y, Fard A, Galeo A, Hutchinson H G, Vermani P, Dodge G R, Hall D J, Shaheen F, Zalewski A
Division of Cardiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Circulation. 1994 Aug;90(2):944-51. doi: 10.1161/01.cir.90.2.944.
Smooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-myc proto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-myc antisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries.
First, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-myc antisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-myc antisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-myc antisense oligomer administration. Maximal neointimal area was reduced from 0.80 +/- 0.17 mm2 in the control group (n = 12) to 0.24 +/- 0.06 mm2 in the antisense-treated group (n = 13, P < .01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P < .01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64 +/- 6% in the control group to 81 +/- 5% in the antisense-treated group (P < .05).
(1) Single transcatheter administration allowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-myc antisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-myc proto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.
平滑肌细胞增殖和细胞外基质积聚是导致血管再狭窄的主要机制。我们之前已经证明了靶向c-myc原癌基因的反义寡核苷酸对人平滑肌细胞的生长抑制作用。本研究的目的是调查c-myc反义寡核苷酸是否能减少球囊剥脱的猪冠状动脉中的新生内膜形成。
首先，反映合成功能的I型胶原合成在猪血管平滑肌细胞中经c-myc反义寡核苷酸处理后显著减少，且与生长抑制无关。这些体外效应为在体内评估c-myc反义寡核苷酸预防新生内膜提供了理论依据。其次，确定了将寡核苷酸经导管单次递送至剥脱的猪冠状动脉的效率。尽管局部给药后血浆清除迅速，但寡核苷酸在注射部位持续存在至少3天，其在注射部位的浓度比外周器官中的浓度高出数倍。第三，在经导管给予c-myc反义寡核苷酸1个月后，对球囊剥脱的冠状动脉进行形态计量分析。对照组（n = 12）的最大新生内膜面积为0.80±0.17mm²，反义治疗组（n = 13，P <.01）降至0.24±0.06mm²。同样，反义治疗组的最大新生内膜厚度也显著降低（P <.01）。剥脱损伤后血管重塑的这些变化导致残余管腔从对照组的64±6%增加到反义治疗组的81±5%（P <.05）。
（1）经导管单次给药可将寡核苷酸腔内递送至冠状动脉损伤部位。（2）c-myc反义寡核苷酸减少了剥脱冠状动脉中新生内膜的形成，这意味着该方法在预防冠状动脉再狭窄方面具有治疗潜力。（3）据推测，c-myc原癌基因参与血管重塑过程，调节平滑肌细胞增殖和细胞外基质合成。
