Köhler Ralf, Wulff Heike, Eichler Ines, Kneifel Marlene, Neumann Daniel, Knorr Andrea, Grgic Ivica, Kämpfe Doris, Si Han, Wibawa Judith, Real Robert, Borner Klaus, Brakemeier Susanne, Orzechowski Hans-Dieter, Reusch Hans-Peter, Paul Martin, Chandy K George, Hoyer Joachim
Department of Nephrology, Benjamin Franklin Medical Center, Berlin, Germany.
Circulation. 2003 Sep 2;108(9):1119-25. doi: 10.1161/01.CIR.0000086464.04719.DD. Epub 2003 Aug 25.
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 (KCa) contribute to intimal hyperplasia and vascular restenosis.
Function and expression of KCa 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 KCa (BKCa) channels. Two weeks after BCI, expression of BKCa was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance KCa (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 approximately 40% 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.
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.
血管成形术可刺激血管平滑肌细胞（VSMC）的增殖和迁移，导致内膜增厚和血管再狭窄。在球囊导管损伤（BCI）大鼠模型中，我们研究了钙激活钾通道（KCa）表达的改变是否促成内膜增生和血管再狭窄。
通过单细胞逆转录聚合酶链反应（RT-PCR）和膜片钳分析相结合的方法，对成熟中膜和内膜VSMC中KCa的功能和表达进行原位表征。成熟中膜VSMC仅表达大电导KCa（BKCa）通道。BCI两周后，内膜VSMC中BKCa的表达显著降低，而中电导KCa（IKCa1）通道的表达上调。在主动脉VSMC细胞系A7r5中，表皮生长因子（EGF）诱导IKCa1上调，且选择性IKCa1阻滞剂TRAM-34可抑制EGF刺激的增殖。每日给大鼠体内注射TRAM-34，在BCI后1周、2周和6周时，内膜增生显著减少约40%。相关化合物克霉唑治疗两周同样有效。内膜增生的减少伴随着内膜细胞含量的降低，细胞凋亡率和胶原含量无变化。
向IKCa1表达的转变可能促进内膜VSMC过度增殖。因此，阻断IKCa1可能代表一种预防血管成形术后再狭窄的新治疗策略。
