Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis
Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis
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DOI：
10.1161/01.cir.0000086464.04719.dd
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发表时间：
2003-09-02
期刊：
影响因子：
37.8
通讯作者：
Hoyer, J
中科院分区：
文献类型：
--
作者：
Köhler, R;Wulff, H;Hoyer, J
血管成形术刺激血管平滑肌细胞（VSMC）增殖和迁移，导致新生内膜增厚和血管再狭窄。在大鼠模型的球囊导管损伤（BCI），我们调查是否在表达的Ca 2+激活的K+通道（K-Ca）的改变，有助于内膜增生和血管restenosis.Methods和Results-Function和表达的K-Ca在成熟的中膜和新生内膜VSMC的特点是在原位结合单细胞RT-PCR和膜片钳分析。成熟中膜VSMC仅表达大电导钾钙通道（BKCa）。BCI后2周，新生内膜VSMC中BKCa的表达显著降低，而中电导K-Ca（IKCa 1）通道的表达上调。在主动脉VSMC细胞系中，A7 r5表皮生长因子（EGF）诱导的IKCa 1上调和EGF刺激的增殖被选择性IKCa 1阻断剂TRAM-34抑制。在BCI后的1、2和6周，每天向大鼠体内施用TRAM-34显著减少内膜增生约40%。用相关化合物克霉唑治疗两周同样有效。减少内膜增生伴随着减少的新生内膜细胞含量，细胞凋亡率或胶原蛋白含量没有变化。结论-IKCa 1表达的开关可能会促进过度的新生内膜VSMC增殖。因此，阻断IKCa 1可能代表一种新的治疗策略，以防止血管成形术后再狭窄。
Background-Angioplasty stimulates proliferation and migration of vascular smooth muscle cells (VSMC), leading to neointimal thickening and vascular restenosis. In a rat model of balloon catheter injury (BCI), we investigated whether alterations in expression of Ca2+-activated K+ channels (K-Ca) contribute to intimal hyperplasia and vascular restenosis.Methods and Results-Function and expression of K-Ca in mature medial and neointimal VSMC were characterized in situ by combined single-cell RT-PCR and patch-clamp analysis. Mature medial VSMC exclusively expressed large-conductance K-Ca (BKCa) channels. Two weeks after BCI, expression of BKCa was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance K-Ca (IKCa1) channels was upregulated. In the aortic VSMC cell line, A7r5 epidermal growth factor (EGF) induced IKCa1 upregulation and EGF-stimulated proliferation was suppressed by the selective IKCa1 blocker TRAM-34. Daily in vivo administration of TRAM-34 to rats significantly reduced intimal hyperplasia by approximate to40% at 1, 2, and 6 weeks after BCI. Two weeks of treatment with the related compound clotrimazole was equally effective. Reduction of intimal hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content.Conclusions-The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.