Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits.
Effect of thrombin inhibition with desulfatohirudin on early kinetics of cellular proliferation after balloon angioplasty in atherosclerotic rabbits.
复制标题
脱硫水蛭素抑制凝血酶对动脉粥样硬化兔球囊血管成形术后早期细胞增殖动力学的影响。
DOI：
10.1161/01.cir.93.6.1194
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发表时间：
1996
期刊：
影响因子：
37.8
通讯作者：
Sarembock,IJ
中科院分区：
文献类型：
--
作者：
Ragosta,M;Barry,WL;Gimple,LW;Gertz,SD;McCoy,KW;Stouffer,GA;McNamara,CA;Powers,ER;Owens,GK;Sarembock,IJ
背景凝血酶可能在血管成形术后再狭窄中发挥关键作用。水蛭素是一种有效的凝血酶抑制剂，可减少兔动脉粥样硬化模型血管成形术后斑块引起的管腔狭窄。由于细胞增殖被认为是再狭窄的重要机制，并且凝血酶在体外已被证明是一种有效的平滑肌细胞有丝分裂原，因此我们推测水蛭素通过抑制斑块限制管腔狭窄的作用机制是通过抑制细胞增殖而发生的。 方法和结果在 108 只兔子中诱导股动脉粥样硬化，并进行球囊血管成形术。在血管成形术中，第 1 组兔子 (n=38) 接受 2 小时水蛭素输注治疗，第 2 组兔子 (n=41) 接受肝素治疗。第3组兔子（n = 29）用水蛭素（n = 15）或肝素（n = 14）治疗，并在7或28天处死，以使用溴脱氧尿苷标记确定斑块和细胞增殖引起的横截面积缩小。血管成形术后29、71或167小时，第1组和第2组兔注射3H-胸苷，1小时后处死，测定标记指标。在30小时（0.06±0.05 vs. 0.01±0.01，P <.01）和72小时（0.10±0.06 vs. 0.004±0.004,P<.01)。 7 天时，标记细胞指数与基线相似（0.04±0.03 与 0.01±0.01，P=.12）。水蛭素对所研究的任何时间点的 3 H-胸苷标记指数没有影响，尽管事实是，第 3 组兔子中的水蛭素治疗在血管成形术后第 7 天和第 28 天均导致斑块导致的横截面积缩小程度较小（第 7 天为 41±16 与 24±12，第 28 天为 60±21 与 44±17，肝素与水蛭素；P<.03)。结论球囊血管成形术导致细胞增殖显着增加，并在 72 小时达到峰值。 2小时输注水蛭素未能减少早期3 H-胸苷标记，这表明在该动物模型中，血管成形术后前7天内抑制细胞增殖并不是水蛭素在球囊血管成形术后28天发挥限制斑块管腔狭窄作用的主要机制。
BackgroundThrombin may have a pivotal role in restenosis after angioplasty. Hirudin, a potent thrombin inhibitor, reduces luminal narrowing by plaque after angioplasty in a rabbit model of atherosclerosis. Because cellular proliferation is believed to be an important mechanism for restenosis and thrombin has been shown to be a potent smooth muscle cell mitogen in vitro, we hypothesized that the mechanism of the effect of hirudin on limiting luminal narrowing by plaque occurs via inhibition of cellular proliferation.Methods and ResultsFemoral atherosclerosis was induced in 108 rabbits, and balloon angioplasty was performed. At angioplasty, group 1 rabbits (n=38) were treated with a 2-hour infusion of hirudin, and group 2 rabbits (n=41) were treated with heparin. Group 3 rabbits (n=29) were treated with hirudin (n=15) or heparin (n=14) and killed at 7 or 28 days to determine cross-sectional area narrowing by plaque and cellular proliferation with the use of bromodeoxyuridine labeling. At 29, 71, or 167 hours after angioplasty, group 1 and 2 rabbits were injected with3H-thymidine and killed 1 hour later, and labeling indexes were determined. A significant increase in the index of3H-thymidine–labeled nuclei was observed in the intima of “ballooned” arteries compared with “nonballooned” atherosclerotic arteries at both 30 hours (0.06±0.05 versus 0.01±0.01,P<.01) and 72 hours (0.10±0.06 versus 0.004±0.004,P<.01). By 7 days, the index of labeled cells was similar to baseline (0.04±0.03 versus 0.01±0.01,P=.12). Hirudin had no effect on the3H-thymidine labeling indexes at any of the time points studied despite the fact that hirudin treatment in group 3 rabbits resulted in less cross-sectional area narrowing by plaque at both 7 and 28 days after angioplasty (41±16 versus 24±12 at 7 days and 60±21 versus 44±17 at 28 days, heparin versus hirudin;P<.03).ConclusionsBalloon angioplasty resulted in a marked increase in cellular proliferation that peaked at 72 hours. A 2-hour infusion of hirudin failed to reduce early3H-thymidine labeling, suggesting that inhibition of cell proliferation within the first 7 days after angioplasty is not the predominant mechanism by which hirudin exerts its effect on limiting luminal narrowing by plaque 28 days after balloon angioplasty in this animal model.