Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates.
Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates.
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金属蛋白酶抑制以及动脉粥样硬化灵长类动物对血管成形术和支架置入术的反应。
DOI：
10.1161/hq0102.101129
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
Geary,RandolphL
中科院分区：
文献类型：
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作者：
Cherr,GregoryS;Motew,StephenJ;Travis,JeffreyA;Fingerle,Juergen;Fisher,Larry;Brandl,Mike;Williams,JKoudy;Geary,RandolphL
血管成形术后再狭窄的决定因素包括收缩性重塑和内膜增生。这两个过程都需要大量的基质周转，因此基质金属蛋白酶（MMPs）已成为抗再狭窄治疗的潜在靶点。我们研究了RO 113 -2908，一种广谱MMP抑制剂（MMPI），对动脉粥样硬化食蟹猴髂动脉血管成形术和支架植入术的反应的影响。血管造影测量管腔直径（LD），并在4周灌注固定后评估动脉壁几何形状。在皮下聚乙烯醇圆盘中测量血管生成。治疗提供了显著的全身MMP抑制活性（血清对25 nmol/L MMP-12的抑制率为97±2.2%），并抑制了血管生成（P=0.007）。相比之下，血管成形术后4周，LD的增益损失（P=0.73）和收缩性重塑（外弹性膜面积比[损伤/未损伤×100]：MMPI，106.3±9.6% vs对照组，119.9±7.2%;P=0.27）没有实质性改善。治疗也未能减少血管成形术（内膜面积[mm 2]：1.4±0.3 vs 1.6± 0.2，P =0.65）或支架置入术（2.4±0.2 vs 2.8± 0.2，P =0.12）后的内膜增生。总之，在动脉粥样硬化灵长类动物中，抑制MMP活性可减少血管生成，但不能防止血管成形术和支架植入术后的收缩性重塑或内膜增生。需要进一步的研究来确定血管成形术后愈合动脉粥样硬化动脉的关键基质降解蛋白酶谱。
Determinants of restenosis after angioplasty include constrictive remodeling and intimal hyperplasia. Both processes require extensive matrix turnover, so matrix metalloproteinases (MMPs) have become potential targets of antirestenosis therapies. We studied the effects of RO113-2908, a broad-spectrum MMP inhibitor (MMPI), on the response to iliac artery angioplasty and stenting in atherosclerotic cynomolgus monkeys. Lumen diameter (LD) was measured angiographically, and artery wall geometry was assessed after perfusion-fixation at 4 weeks. Angiogenesis was measured in subcutaneous polyvinyl alcohol disks. Treatment provided significant, systemic MMP inhibitory activity (97±2.2% inhibition of 25 nmol/L MMP-12 by serum) and inhibited angiogenesis (P=0.007). In contrast, loss of gain in LD (P=0.73) and constrictive remodeling (external elastic lamina area ratio [injured/uninjured×100]: MMPI, 106.3±9.6% vs control, 119.9±7.2%;P=0.27) were not substantially improved 4 weeks after angioplasty. Treatment also failed to reduce intimal hyperplasia after angioplasty (intimal area [mm2]: 1.4±0.3 vs 1.6±0.2,P=0.65) or stenting (2.4±0.2 vs 2.8±0.2,P=0.12). In summary, inhibition of MMP activity reduced angiogenesis but failed to prevent constrictive remodeling or intimal hyperplasia after angioplasty and stenting in atherosclerotic primates. Additional research is needed to define the spectrum of matrix-degrading proteases critical in healing atherosclerotic arteries after angioplasty.