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Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1084-1089
Published online before print February 28, 2008, doi: 10.1161/ATVBAHA.107.155796
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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 KCa3.1 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 (KCa3.1) 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 KCa3.1 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 KCa3.1 blocker TRAM-34. Expression of KCa3.1, 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. KCa3.1, 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 KCa3.1 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 KCa3.1 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 KCa3.1 in the regulation of coronary smooth muscle cell (SMC) phenotypic modulation in a swine model of postangioplasty restenosis. Blockade of KCa3.1 by delivery of TRAM-34 via balloon catheter prevented SMC phenotypic modulation and limited subsequent restenosis.


Key Words: KCa3.1 • TRAM-34 • coronary smooth muscle • balloon angioplasty • phenotypic modulation


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