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Blockers of K V 1.3 channel suppress smooth muscle response to injury and neointimal hyperplasia
Author(s) -
Cheong Alex,
Sukumar Piruthivi,
Kumar Bhaksar,
Li Jing,
Bingham Andrew J,
Zeng Fanning,
Munsch Christopher,
Porter Karen E,
Wood Ian C,
Beech David J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a69-c
Subject(s) - vascular smooth muscle , downregulation and upregulation , neointimal hyperplasia , hyperplasia , cell growth , microbiology and biotechnology , myocyte , medicine , phenotype , cell , cancer research , potassium channel , endocrinology , restenosis , biology , smooth muscle , gene , stent , biochemistry
In vascular injury, the mechanisms responsible for contractile smooth muscle phenotype is altered, leading to vascular smooth muscle cell (VSMC) proliferation and vascular diseases such as neointimal hyperplasia. Analysis of mouse VSMC mRNA revealed the selective upregulation of KCNA3 gene (encoding K V 1.3) when the cells switch phenotype. We here provide evidence for its role in vascular proliferation. Using a linear wound assay, we show that K V 1.3 blockers margatoxin and correolide compound C inhibited cell motility in both mouse and human VSMC. Furthermore K V 1.3 protein is selectively localised to smooth muscle cells grown in situ as neointimal formations in human saphenous veins obtained at coronary artery bypass surgery. Application of K V 1.3 blockers reduced the neointimal formation and inhibited a voltage‐dependent potassium current in human VSMC. We previously showed that downregulated REST transcription factor during phenotypic switching enables KCNN4 expression (Cheong et al, 2005). Here we reveal that KCNA3 also has a REST binding site and that there is enhanced KCNA3 expression in response to dominant‐negative REST mutant. These data indicate that K V 1.3 is upregulated in VSMC proliferation and that existing blockers of K V 1.3 might have a therapeutic role in diseases caused or exacerbated by VSMC proliferation. Funded by the BHF, MRC and Wellcome Trust.