Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers

Alex Cheong, Jing Li, Piruthivi Sukumar, Bhaskar Kumar, Fanning Zeng, Kirsten Riches, Christopher Munsch, Ian C. Wood, Karen E. Porter, David J. Beech

Research output: Contribution to journalArticle

Abstract

Aim - The aim of the study was to determine the potential for KV1 potassium channel blockers as inhibitors of human neoinitimal hyperplasia.
Methods and results - Blood vessels were obtained from patients or mice and studied in culture. Reverse transcriptasepolymerase chain reaction and immunocytochemistry were used to detect gene expression. Whole-cell patch-clamp, intracellular calcium measurement, cell migration assays, and organ culture were used to assess channel function.  KV1.3 was unique among the  KV1 channels in showing preserved and up-regulated expression when the vascular smooth muscle cells switched to the proliferating phenotype. There was strong expression in neointimal formations. Voltage-dependent potassium current in proliferating cells was sensitive to three different blockers of  KV1.3 channels. Calcium entry was also inhibited. All three blockers reduced vascular smooth muscle cell migration and the effects were non-additive. One of the blockers (margatoxin) was highly potent, suppressing cell migration with an IC of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia.
Conclusion - KV1.3 potassium channels are functional in proliferating mouse and human vascular smooth muscle cells and have positive effects on cell migration. Blockers of the channels may be useful as inhibitors of neointimal hyperplasia and other unwanted vascular remodelling events.

LanguageEnglish
Pages282-289
Number of pages8
JournalCardiovascular Research
Volume89
Issue number2
Early online date29 Sep 2010
DOIs
Publication statusPublished - Feb 2011

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Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Hyperplasia
Kv1.3 Potassium Channel
Cell Migration Assays
Potassium Channel Blockers
Calcium
Organ Culture Techniques
Blood Vessels
Veins
Potassium
Immunohistochemistry
Phenotype
Gene Expression

Bibliographical note

The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Keywords

  • cell migration
  • vascular smooth muscle cell
  • neointimal hyperplasia
  • potassium channels

Cite this

Cheong, Alex ; Li, Jing ; Sukumar, Piruthivi ; Kumar, Bhaskar ; Zeng, Fanning ; Riches, Kirsten ; Munsch, Christopher ; Wood, Ian C. ; Porter, Karen E. ; Beech, David J. / Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers. In: Cardiovascular Research. 2011 ; Vol. 89, No. 2. pp. 282-289.
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Cheong, A, Li, J, Sukumar, P, Kumar, B, Zeng, F, Riches, K, Munsch, C, Wood, IC, Porter, KE & Beech, DJ 2011, 'Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers' Cardiovascular Research, vol. 89, no. 2, pp. 282-289. https://doi.org/10.1093/cvr/cvq305

Potent suppression of vascular smooth muscle cell migration and human neointimal hyperplasia by KV1.3 channel blockers. / Cheong, Alex; Li, Jing; Sukumar, Piruthivi; Kumar, Bhaskar; Zeng, Fanning; Riches, Kirsten; Munsch, Christopher; Wood, Ian C.; Porter, Karen E.; Beech, David J.

In: Cardiovascular Research, Vol. 89, No. 2, 02.2011, p. 282-289.

Research output: Contribution to journalArticle

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AU - Cheong, Alex

AU - Li, Jing

AU - Sukumar, Piruthivi

AU - Kumar, Bhaskar

AU - Zeng, Fanning

AU - Riches, Kirsten

AU - Munsch, Christopher

AU - Wood, Ian C.

AU - Porter, Karen E.

AU - Beech, David J.

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N2 - Aim - The aim of the study was to determine the potential for KV1 potassium channel blockers as inhibitors of human neoinitimal hyperplasia. Methods and results - Blood vessels were obtained from patients or mice and studied in culture. Reverse transcriptasepolymerase chain reaction and immunocytochemistry were used to detect gene expression. Whole-cell patch-clamp, intracellular calcium measurement, cell migration assays, and organ culture were used to assess channel function.  KV1.3 was unique among the  KV1 channels in showing preserved and up-regulated expression when the vascular smooth muscle cells switched to the proliferating phenotype. There was strong expression in neointimal formations. Voltage-dependent potassium current in proliferating cells was sensitive to three different blockers of  KV1.3 channels. Calcium entry was also inhibited. All three blockers reduced vascular smooth muscle cell migration and the effects were non-additive. One of the blockers (margatoxin) was highly potent, suppressing cell migration with an IC of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia. Conclusion - KV1.3 potassium channels are functional in proliferating mouse and human vascular smooth muscle cells and have positive effects on cell migration. Blockers of the channels may be useful as inhibitors of neointimal hyperplasia and other unwanted vascular remodelling events.

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