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.

Original languageEnglish
Pages (from-to)282-289
Number of pages8
JournalCardiovascular Research
Volume89
Issue number2
Early online date29 Sep 2010
DOIs
Publication statusPublished - Feb 2011

Bibliographical note

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Keywords

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

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