Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

Ralf Köhler, Heike Wulff, Ines Eichler, Marlene Kneifel, Daniel Neumann, Andrea Knorr, Ivica Grgic, Doris Kämpfe, Han Si, Judith Wibawa, Robert Real, Klaus Borner, Susanne Brakemeier, Hans-Dieter Orzechowski, Hans-Peter Reusch, Martin Paul, K George Chandy, Joachim Hoyer

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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 (KCa) contribute to intimal hyperplasia and vascular restenosis. METHODS AND RESULTS: 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. 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.
OriginalsprogEngelsk
TidsskriftCirculation
Vol/bind108
Udgave nummer9
Sider (fra-til)1119-25
Antal sider6
ISSN0009-7322
DOI
StatusUdgivet - 2003

Fingeraftryk

Vascular Smooth Muscle
Hyperplasia
Catheters
Epidermal Growth Factor
Wounds and Injuries
Clotrimazole
Up-Regulation
Cell Proliferation
Apoptosis
Cell Line
Polymerase Chain Reaction

Citer dette

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. / Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. I: Circulation. 2003 ; Bind 108, Nr. 9. s. 1119-25.
@article{621521b0b95e11deab49000ea68e967b,
title = "Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis",
abstract = "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 (KCa) contribute to intimal hyperplasia and vascular restenosis. METHODS AND RESULTS: 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. 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.",
author = "Ralf K{\"o}hler and Heike Wulff and Ines Eichler and Marlene Kneifel and Daniel Neumann and Andrea Knorr and Ivica Grgic and Doris K{\"a}mpfe and Han Si and Judith Wibawa and Robert Real and Klaus Borner and Susanne Brakemeier and Hans-Dieter Orzechowski and Hans-Peter Reusch and Martin Paul and Chandy, {K George} and Joachim Hoyer",
year = "2003",
doi = "10.1161/01.CIR.0000086464.04719.DD",
language = "English",
volume = "108",
pages = "1119--25",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "9",

}

Köhler, R, Wulff, H, Eichler, I, Kneifel, M, Neumann, D, Knorr, A, Grgic, I, Kämpfe, D, Si, H, Wibawa, J, Real, R, Borner, K, Brakemeier, S, Orzechowski, H-D, Reusch, H-P, Paul, M, Chandy, KG & Hoyer, J 2003, 'Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis', Circulation, bind 108, nr. 9, s. 1119-25. https://doi.org/10.1161/01.CIR.0000086464.04719.DD

Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis. / 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.

I: Circulation, Bind 108, Nr. 9, 2003, s. 1119-25.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

AU - Köhler, Ralf

AU - Wulff, Heike

AU - Eichler, Ines

AU - Kneifel, Marlene

AU - Neumann, Daniel

AU - Knorr, Andrea

AU - Grgic, Ivica

AU - Kämpfe, Doris

AU - Si, Han

AU - Wibawa, Judith

AU - Real, Robert

AU - Borner, Klaus

AU - Brakemeier, Susanne

AU - Orzechowski, Hans-Dieter

AU - Reusch, Hans-Peter

AU - Paul, Martin

AU - Chandy, K George

AU - Hoyer, Joachim

PY - 2003

Y1 - 2003

N2 - 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 (KCa) contribute to intimal hyperplasia and vascular restenosis. METHODS AND RESULTS: 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. 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.

AB - 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 (KCa) contribute to intimal hyperplasia and vascular restenosis. METHODS AND RESULTS: 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. 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.

U2 - 10.1161/01.CIR.0000086464.04719.DD

DO - 10.1161/01.CIR.0000086464.04719.DD

M3 - Journal article

VL - 108

SP - 1119

EP - 1125

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -