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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1084.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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; H. Wulff; G. Raman; A. Cheong; D.K. Bowles

From the Department of Biomedical Sciences (D.L.T., D.K.B.), Dalton Cardiovascular Research Center (D.K.B.), and Research Angiography Core (D.L.T., D.K.B.), University of Missouri, Columbia; the Cardiovascular Division (B.R.W.), Biomedical Engineering and The Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville; the Department of Pharmacology (H.W., G.R.), University of California, Davis; and the Institute of Membranes and Systems Biology (A.C.), University of Leeds, UK.

Correspondence to Doug Bowles, E102 Veterinary Medicine Building, 1600 E. Rollins, University of Missouri, Columbia, MO 65211. E-mail BowlesD{at}missouri.edu

Objective— We previously demonstrated that upregulation of intermediate-conductance Ca²⁺-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.

The objective of the present study was to determine the role of K_Ca3.1 in the regulation of coronary smooth muscle cell (SMC) phenotypic modulation in a swine model of postangioplasty restenosis. Blockade of K_Ca3.1 by delivery of TRAM-34 via balloon catheter prevented SMC phenotypic modulation and limited subsequent restenosis.

Key Words: K_Ca3.1 • TRAM-34 • coronary smooth muscle • balloon angioplasty • phenotypic modulation

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Preventing Stenosis by Local Inhibition of K_Ca3.1: A Finger on the Phenotypic Switch

Karen M. Lounsbury
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