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

Cardiovasc Res. 2011 Feb 1;89(2):282-9. doi: 10.1093/cvr/cvq305. Epub 2010 Sep 29.

Abstract

Aim: The aim of the study was to determine the potential for K(V)1 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 transcriptase-polymerase 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. K(V)1.3 was unique among the K(V)1 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 K(V)1.3 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(50) of 85 pM. Two of the blockers were tested in organ-cultured human vein samples and both inhibited neointimal hyperplasia.

Conclusion: K(V)1.3 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism
  • Calcium / metabolism
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Ficusin / pharmacology
  • Humans
  • Hyperplasia
  • Immunohistochemistry
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Kv1.3 Potassium Channel / genetics
  • Kv1.3 Potassium Channel / metabolism
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / pharmacology*
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Saphenous Vein / drug effects
  • Saphenous Vein / metabolism
  • Scorpion Venoms / pharmacology
  • Time Factors
  • Triterpenes / pharmacology
  • Tunica Intima / drug effects*
  • Tunica Intima / metabolism
  • Tunica Intima / pathology

Substances

  • 5-(4-phenylbutoxy)psoralen
  • KCNA3 protein, human
  • Kcna3 protein, mouse
  • Kv1.3 Potassium Channel
  • Potassium Channel Blockers
  • RNA, Messenger
  • Scorpion Venoms
  • Triterpenes
  • correolide
  • margatoxin
  • Ficusin
  • Calcium