Transcatheter Delivery of c‐myc Antisense Oligomers Reduces Neointimal Formation in a Porcine Model of Coronary Artery Balloon Injury
Transcatheter Delivery of c‐myc Antisense Oligomers Reduces Neointimal Formation in a Porcine Model of Coronary Artery Balloon Injury
复制标题
经导管输送 c-myc 反义寡聚物可减少猪冠状动脉球囊损伤模型中的新内膜形成
作者：
Yi Shi;A. Fard;Anthony Galeo;H. Hutchinson;Pawan Vermani;G. R. Dodge;D. Hall;F. Shaheen;A. Zalewski
研究背景平滑的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针对c-myc原癌基因的反义寡聚物对人血管平滑肌细胞的生长抑制作用。本研究的目的是研究c-myc反义寡聚体是否能减少球囊剥离的猪冠状动脉新生内膜的形成。方法和结果首先，反映合成功能的I型胶原合成在c-myc反义寡聚体作用下显著减少，而不受生长抑制的影响。这些体外效应为评估c-myc反义寡聚体在体内预防新生内膜的作用提供了理论基础。其次，测定了低聚物单次经导管注入猪冠状动脉的效率。尽管局部给药后血浆迅速清除，但低聚物在注射部位至少持续了3天，超过其在周围器官中浓度的几倍。第三，在经导管注射c-myc AN-V寡聚物后1个月，对球囊剥离的冠状动脉进行形态计量分析。最大新生内膜面积从对照组(n=12)的0.80±0.17mm2减少到反义组(n=13)的0.24±0.06mm2(P<0.01)。同样，反义治疗组的最大新生内膜厚度显著减少(P<；.01)。这些裸露损伤后血管重构的改变导致残余管腔从对照组的±6%增加到反义治疗组的81±5%(P<；0.05)。结论(1)低聚物可经导管一次性腔内给药至冠脉损伤部位。(2)C-myc反义寡聚物可减少裸露冠状动脉内膜形成，提示C-myc反义寡聚体具有预防冠状动脉再狭窄的治疗潜力。(3)推测c-myc原癌基因参与了血管重塑、调节血管平滑肌细胞增殖和细胞外基质合成的过程。
BackgroundSmooth 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. Methods and ResultsFirst, 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 an-V tisense 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). Conclusions(1) Single transcatheter administration al-lowed 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.
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DOI：
10.1242/dev.110.3.769
发表时间：
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期刊：
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影响因子：
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DOI：
--
发表时间：
1991
期刊：
The American journal of pathology
影响因子：
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作者：
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影响因子：
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