Effects of statins on vascular function of endothelin-1
Effects of statins on vascular function of endothelin-1
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DOI：
10.1038/sj.bjp.0706114
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发表时间：
2005-03-01
影响因子：
7.3
通讯作者：
Vollrath, B
中科院分区：
文献类型：
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作者：
Mraiche, F;Cena, J;Vollrath, B
1他汀类药物可抑制内皮细胞前内皮素原-1（ET-1）基因的转录，但对ET-1血管功能的影响尚未见报道。因此，我们研究了他汀类药物对ET-1介导的血管平滑肌收缩和DNA合成的影响。将他汀类药物对ET-1诱导的收缩的作用与去甲肾上腺素（NA）和KCl介导的收缩作用进行比较。2辛伐他汀（SV）诱导ET-1（10 nM）介导的强直性收缩的浓度依赖性舒张（IC 50值为1.3 μ M）。在用NA（0.1 μ M）和KCl（60 mM）预收缩的环中也观察到松弛。3内皮剥脱或L-NAME预处理不能阻止SV的舒张作用，但能降低SV的舒张活性。4 SV阻止了由ET-1和KCl在主动脉匀浆中引起的Rho激活，如通过Rho下拉分析所评估的。5 Rho激酶抑制剂HA-1077模拟SV对由ET-1、NA和KCl诱导的紧张性收缩的作用。6用Kv通道抑制剂4-氨基吡啶预处理，减弱了SV舒张由ET-1和NA介导的收缩的能力。7在静止的VSM细胞中，SV显著抑制ET-1刺激的DNA合成和Rho易位，分别通过[H-3]胸苷掺入和Western印迹进行评估。8 GGTI- 297或HA-1077处理对Rho香叶基香叶基化的抑制，模拟SV对ET-1刺激的DNA合成的影响。9结果表明，他汀类药物有效抑制ET-1-介导的收缩和DNA合成通过多种机制。他汀类药物的临床益处可能部分来自其对ET-1的血管功能的影响。
1 Although statins have been reported to inhibit the prepro-endothelin-1 (ET-1) gene transcription in endothelial cells, their effects on the vascular function of ET-1 have not been explored. We, therefore, examined the effects of statins on contraction and DNA synthesis mediated by ET-1 in vascular smooth muscle. The effects of statins on contraction induced by ET-1 were compared to those mediated by noradrenaline (NA) and KCl.2 Simvastatin (SV) induced a concentration-dependent relaxation of tonic contraction mediated by ET-1 (10 nM) (IC50 value of 1.3 mu M). The relaxation was also observed in rings precontracted with NA (0.1 mu M) and KCl (60 mM). In contrast, pravastatin did not have any effect on the contractions.3 Endothelial denudation or pretreatment with L-NAME did not prevent the relaxation, but did reduce the relaxant activity of SV. 4 SV prevented Rho activation caused by ET-1 and KCl in aortic homogenates, as assessed by a Rho pulldown assay.5 The Rho kinase inhibitor HA-1077 mimicked the effects of SV on tonic contractions induced by ET-1, NA and KCl.6 Pretreatment with the Kv channels inhibitor, 4-aminopyridine, attenuated the ability of SV to relax contractions mediated by ET-1 and NA.7 In quiescent VSM cells, SV significantly inhibited DNA synthesis and Rho translocation stimulated by ET-1, as assessed by [H-3] thymidine incorporation and Western blot, respectively.8 Inhibition of Rho geranylgeranylation by GGTI- 297, or treatment with HA-1077, mimicked the effects of SV on DNA synthesis stimulated by ET-1.9 The results show that the statin potently inhibits both ET-1-mediated contraction and DNA synthesis via multiple mechanisms. Clinical benefits of statins may result, in part, from their effects on vascular function of ET-1.