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

Research output: Contribution to journalArticle

189 Citations (Scopus)

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 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 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 ≈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 IKCal expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.

Original languageEnglish (US)
Pages (from-to)1119-1125
Number of pages7
JournalCirculation
Volume108
Issue number9
DOIs
StatePublished - Sep 2 2003

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Intermediate-Conductance Calcium-Activated Potassium Channels
Vascular Smooth Muscle
Smooth Muscle Myocytes
Tunica Intima
Hyperplasia
Catheters
Angioplasty
Epidermal Growth Factor
Blood Vessels
Wounds and Injuries
Therapeutics
Clotrimazole
Calcium-Activated Potassium Channels
Up-Regulation
Collagen
Cell Proliferation
Apoptosis
Cell Line
Polymerase Chain Reaction

Keywords

  • Angioplasty
  • Ion channels
  • Restenosis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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.

In: Circulation, Vol. 108, No. 9, 02.09.2003, p. 1119-1125.

Research output: Contribution to journalArticle

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, HD, Reusch, HP, Paul, M, Chandy, KG & Hoyer, J 2003, 'Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis', Circulation, vol. 108, no. 9, pp. 1119-1125. https://doi.org/10.1161/01.CIR.0000086464.04719.DD
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. In: Circulation. 2003 ; Vol. 108, No. 9. pp. 1119-1125.
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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 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 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 ≈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 IKCal expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.",
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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 - 2003/9/2

Y1 - 2003/9/2

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 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 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 ≈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 IKCal 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 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 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 ≈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 IKCal expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.

KW - Angioplasty

KW - Ion channels

KW - Restenosis

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