Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis.
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.


RESULTS
Function and expression of KCa 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 approximately 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 IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent restenosis after angioplasty.
Köhler
Ralf
R
Department of Nephrology, Benjamin Franklin Medical Center, Berlin, Germany. koe@zedat.fu-berlin.de
Wulff
Heike
H
Eichler
Ines
I
Kneifel
Marlene
M
Neumann
Daniel
D
Knorr
Andrea
A
Grgic
Ivica
I
Kämpfe
Doris
D
Si
Han
H
Wibawa
Judith
J
Real
Robert
R
Borner
Klaus
K
Brakemeier
Susanne
S
Orzechowski
Hans-Dieter
HD
Reusch
Hans-Peter
HP
Paul
Martin
M
Chandy
K George
KG
Hoyer
Joachim
J
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003022:Clotrimazole / Q000627:therapeutic use; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000166:cytology / Q000473:pathology
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D012333:RNA, Messenger; C411671:TRAM 34; D004815:Epidermal Growth Factor; D003022:Clotrimazole