Moran C S, Campbell J H, Campbell G R
Centre for Research in Vascular Biology, Department of Anatomical Sciences, University of Queensland, Brisbane, Australia.
J Vasc Res. 1997 Sep-Oct;34(5):378-85. doi: 10.1159/000159246.
We have previously shown that human leukaemia inhibitory factor (hLIF) inhibits perivascular cuff-induced neointimal formation in the rabbit carotid artery. Since nitric oxide (NO) is a known inhibitor of smooth muscle growth, NO synthase (NOS) activity in the presence of hLIF was examined in vivo and in vitro. In rabbit aortic smooth muscle cell (SMC) culture, significant NOS activity was observed at 50 pg/ml hLIF, with maximal activity at 5 ng/ml. In the presence of the NOS inhibitor L-NAME, hLIF-induced activation of NOS was greatly decreased, however it was still 63-fold higher than in control (p < 0.05). SMC-DNA synthesis was significantly reduced (-47%) following incubation with hLIF plus L-arginine, the substrate required for NO production (p < 0.05), with no effect observed in the absence of L-arginine. Silastic cuff placement over the right carotid artery of rabbits resulted in a neointima 19.3 +/- 5.4% of total wall cross-sectional area, which was increased in the presence of L-NAME (27.0 +/- 2.0%; p < 0.05) and reduced in the presence of L-arginine (11.3 +/- 2.0%; p < 0.05). The effect of L-arginine was ameliorated by co-administration of L-NAME (16.4 +/- 1.5%). However, administration of L-NAME with hLIF had no effect on the potent inhibition of neointimal formation by hLIF (3.2 +/- 2.5 vs. 2.1 +/- 5.4%, respectively). Similarly, with hLIF administration, NOS activity in the cuffed carotid increased to 269.0 +/- 14.0% of saline-treated controls and remained significantly higher with co-administration of L-NAME (188.5 +/- 14.7%). These results indicate that hLIF causes superinduction of NO by SMC, and that it is, either partially or wholly, through this mechanism that hLIF is a potent inhibitor of neointimal formation in vivo and of smooth muscle proliferation in vitro.
我们之前已经表明，人白血病抑制因子（hLIF）可抑制兔颈动脉血管周围套扎诱导的新生内膜形成。由于一氧化氮（NO）是已知的平滑肌生长抑制剂，因此在体内和体外研究了hLIF存在时的一氧化氮合酶（NOS）活性。在兔主动脉平滑肌细胞（SMC）培养中，在50 pg/ml hLIF时观察到显著的NOS活性，在5 ng/ml时活性最高。在NOS抑制剂L-NAME存在的情况下，hLIF诱导的NOS激活显著降低，但仍比对照高63倍（p<0.05）。与hLIF加L-精氨酸（NO产生所需的底物）孵育后，SMC-DNA合成显著减少（-47%）（p<0.05），在没有L-精氨酸的情况下未观察到影响。在兔右颈动脉上放置硅橡胶套会导致新生内膜占总壁横截面积的19.3±5.4%，在L-NAME存在时增加（27.0±2.0%；p<0.05），在L-精氨酸存在时减少（11.3±2.0%；p<0.05）。L-精氨酸的作用通过联合给予L-NAME而减弱（16.4±1.5%）。然而，L-NAME与hLIF联合给药对hLIF对新生内膜形成的有效抑制没有影响（分别为3.2±2.5%和2.1±5.4%）。同样，给予hLIF后，套扎颈动脉中的NOS活性增加到盐水处理对照的269.0±14.0%，联合给予L-NAME时仍显著更高（188.5±14.7%）。这些结果表明，hLIF导致SMC对NO的超诱导，并且hLIF在体内是新生内膜形成的有效抑制剂以及在体外是平滑肌增殖的有效抑制剂，这一作用部分或全部是通过这一机制实现的。
