Local delivery of the K Ca3.1 blocker, TRAM-34, prevents acute angioplasty-induced coronary smooth muscle phenotypic modulation and limits stenosis

D. L. Tharp, B. R. Wamhoff, Heike Wulff, G. Raman, A. Cheong, D. K. Bowles

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Objective-We previously demonstrated that upregulation of intermediate-conductance Ca 2+-activated K+ channels (K Ca3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective of the present study was to determine the role of K Ca3.1 in the regulation of coronary SMC phenotypic modulation in vivo using a swine model of postangioplasty restenosis. Methods and Results-Balloon angioplasty was performed on coronary arteries of swine using either noncoated or balloons coated with the specific K Ca3.1 blocker TRAM-34. Expression of K Ca3.1, c-jun, c-fos, repressor element-1 silencing transcription factor (REST), smooth muscle myosin heavy chain (SMMHC), and myocardin was measured using qRT-PCR in isolated medial cells 2 hours and 2 days postangioplasty. K Ca3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas REST expression decreased. SMMHC expression was unchanged at 2 hours, but decreased 2 days postangioplasty. Use of TRAM-34 coated balloons prevented K Ca3.1 upregulation and REST downregulation at 2 hours, SMMHC and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty. Immunohistochemical analysis demonstrated corresponding changes at the protein level. Conclusion-Blockade of K Ca3.1 by delivery of TRAM-34 via balloon catheter prevented smooth muscle phenotypic modulation and limited subsequent restenosis.

Original languageEnglish (US)
Pages (from-to)1084-1089
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Balloon angioplasty
  • Coronary smooth muscle
  • K 3.1
  • Phenotypic modulation
  • TRAM-34

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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