This Article Full Text Full Text (PDF) All Versions of this Article: 108/9/1119    most recent 01.CIR.0000086464.04719.DDv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Köhler, R. Articles by Hoyer, J. Search for Related Content PubMed PubMed Citation Articles by Köhler, R. Articles by Hoyer, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CLOTRIMAZOLE Related Collections Restenosis

(Circulation. 2003;108:1119.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Blockade of the Intermediate-Conductance Calcium-Activated Potassium Channel as a New Therapeutic Strategy for Restenosis

Ralf Köhler, PhD; Heike Wulff, PhD; Ines Eichler, MD; Marlene Kneifel; Daniel Neumann; Andrea Knorr; Ivica Grgic; Doris Kämpfe; Han Si, MSc; Judith Wibawa; Robert Real, MD; Klaus Borner, MD; Susanne Brakemeier, MD; Hans-Dieter Orzechowski, MD; Hans-Peter Reusch, MD; Martin Paul, MD; K. George Chandy, MD; Joachim Hoyer, MD

From the Departments of Nephrology (R.K., I.E., M.K., D.N., A.K., I.G., D.K., H.S., J.W., S.B., J.H.), Clinical Pharmacology and Toxicology (R.R., H.D.-O., M.P.), and Clinical Chemistry (K.B.), Benjamin Franklin Medical Center, Berlin, Germany; the Department of Clinical Pharmacology, Ruhr-Universität Bochum, Germany (H.-P.R.); the Department of Physiology and Biophysics (K.G.C.), University of California, Irvine; and the Department of Pharmacology and Toxicology (H.W.), University of California, Davis.

Correspondence to Dr R. Köhler, UKBF, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail koe{at}zedat.fu-berlin.de

Received January 17, 2003; de novo received February 6, 2003; revision received April 24, 2003; accepted April 25, 2003.

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 (K_Ca) contribute to intimal hyperplasia and vascular restenosis.

Methods and Results— Function and expression of K_Ca 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 K_Ca (BK_Ca) channels. Two weeks after BCI, expression of BK_Ca was significantly reduced in neointimal VSMC, whereas expression of intermediate-conductance K_Ca (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 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.

Key Words: angioplasty • restenosis • ion channels

This article has been cited by other articles:

				K. M. Lounsbury Preventing Stenosis by Local Inhibition of KCa3.1: A Finger on the Phenotypic Switch Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1036 - 1038. [Full Text] [PDF]

				D.L. Tharp, B.R. Wamhoff, H. Wulff, G. Raman, A. Cheong, and D.K. Bowles Local Delivery of the KCa3.1 Blocker, TRAM-34, Prevents Acute Angioplasty-Induced Coronary Smooth Muscle Phenotypic Modulation and Limits Stenosis Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1084 - 1089. [Abstract] [Full Text] [PDF]

				K. A. Dora, N. T. Gallagher, A. McNeish, and C. J. Garland Modulation of Endothelial Cell KCa3.1 Channels During Endothelium-Derived Hyperpolarizing Factor Signaling in Mesenteric Resistance Arteries Circ. Res., May 23, 2008; 102(10): 1247 - 1255. [Abstract] [Full Text] [PDF]

				M. C. Shepherd, S. M. Duffy, T. Harris, G. Cruse, M. Schuliga, C. E. Brightling, C. B. Neylon, P. Bradding, and A. G. Stewart KCa3.1 Ca2+Activated K+ Channels Regulate Human Airway Smooth Muscle Proliferation Am. J. Respir. Cell Mol. Biol., November 1, 2007; 37(5): 525 - 531. [Abstract] [Full Text] [PDF]

				N. T. N. Trinh, A. Prive, L. Kheir, J.-C. Bourret, T. Hijazi, M. G. Amraei, J. Noel, and E. Brochiero Involvement of KATP and KvLQT1 K+ channels in EGF-stimulated alveolar epithelial cell repair processes Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L870 - L882. [Abstract] [Full Text] [PDF]

				T. V. Nguyen, H. Matsuyama, J. Baell, B. Hunne, C. J. Fowler, J. E. Smith, K. Nurgali, and J. B. Furness Effects of Compounds That Influence IK (KCNN4) Channels on Afterhyperpolarizing Potentials, and Determination of IK Channel Sequence, in Guinea Pig Enteric Neurons J Neurophysiol, March 1, 2007; 97(3): 2024 - 2031. [Abstract] [Full Text] [PDF]

				D. L. Tharp, B. R. Wamhoff, J. R. Turk, and D. K. Bowles Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2493 - H2503. [Abstract] [Full Text] [PDF]

				G Cruse, S M Duffy, C E Brightling, and P Bradding Functional KCa3.1 K+ channels are required for human lung mast cell migration Thorax, October 1, 2006; 61(10): 880 - 885. [Abstract] [Full Text] [PDF]

				H. Si, W.-T. Heyken, S. E. Wolfle, M. Tysiac, R. Schubert, I. Grgic, L. Vilianovich, G. Giebing, T. Maier, V. Gross, et al. Impaired Endothelium-Derived Hyperpolarizing Factor-Mediated Dilations and Increased Blood Pressure in Mice Deficient of the Intermediate-Conductance Ca2+-Activated K+ Channel Circ. Res., September 1, 2006; 99(5): 537 - 544. [Abstract] [Full Text] [PDF]

				S. Srivastava, K. Ko, P. Choudhury, Z. Li, A. K. Johnson, V. Nadkarni, D. Unutmaz, W. A. Coetzee, and E. Y. Skolnik Phosphatidylinositol-3 Phosphatase Myotubularin-Related Protein 6 Negatively Regulates CD4 T Cells Mol. Cell. Biol., August 1, 2006; 26(15): 5595 - 5602. [Abstract] [Full Text] [PDF]

				G.-R. Li, X.-L. Deng, H. Sun, S. S.M. Chung, H.-F. Tse, and C.-P. Lau Ion Channels in Mesenchymal Stem Cells from Rat Bone Marrow Stem Cells, June 1, 2006; 24(6): 1519 - 1528. [Abstract] [Full Text] [PDF]

				B. R. Wamhoff, D. K. Bowles, and G. K. Owens Excitation-Transcription Coupling in Arterial Smooth Muscle Circ. Res., April 14, 2006; 98(7): 868 - 878. [Abstract] [Full Text] [PDF]

				J. Ledoux, M. E. Werner, J. E. Brayden, and M. T. Nelson Calcium-Activated Potassium Channels and the Regulation of Vascular Tone Physiology, February 1, 2006; 21(1): 69 - 78. [Abstract] [Full Text] [PDF]

				A. Ivanov, V. Gerzanich, S. Ivanova, R. DenHaese, O. Tsymbalyuk, and J. M. Simard Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle J. Physiol., January 1, 2006; 570(1): 73 - 84. [Abstract] [Full Text] [PDF]

				S. Srivastava, P. Choudhury, Z. Li, G. Liu, V. Nadkarni, K. Ko, W. A. Coetzee, and E. Y. Skolnik Phosphatidylinositol 3-Phosphate Indirectly Activates KCa3.1 via 14 Amino Acids in the Carboxy Terminus of KCa3.1 Mol. Biol. Cell, January 1, 2006; 17(1): 146 - 154. [Abstract] [Full Text] [PDF]

				W. F. Jackson Potassium Channels and Proliferation of Vascular Smooth Muscle Cells Circ. Res., December 9, 2005; 97(12): 1211 - 1212. [Full Text] [PDF]

				E. Miguel-Velado, A. Moreno-Dominguez, O. Colinas, P. Cidad, M. Heras, M. T. Perez-Garcia, and J. R. Lopez-Lopez Contribution of Kv Channels to Phenotypic Remodeling of Human Uterine Artery Smooth Muscle Cells Circ. Res., December 9, 2005; 97(12): 1280 - 1287. [Abstract] [Full Text] [PDF]

				H. M. Jones, K. L. Hamilton, and D. C. Devor Role of an S4-S5 Linker Lysine in the Trafficking of the Ca2+-activated K+ Channels IK1 and SK3 J. Biol. Chem., November 4, 2005; 280(44): 37257 - 37265. [Abstract] [Full Text] [PDF]

				M. D Ganfornina, M. T Perez-Garcia, G Gutierrez, E Miguel-Velado, J. R Lopez-Lopez, A Marin, D Sanchez, and C Gonzalez Comparative gene expression profile of mouse carotid body and adrenal medulla under physiological hypoxia J. Physiol., July 15, 2005; 566(2): 491 - 503. [Abstract] [Full Text] [PDF]

				S. Srivastava, Z. Li, L. Lin, G. Liu, K. Ko, W. A. Coetzee, and E. Y. Skolnik The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-Activated K+ Channel KCa3.1 Mol. Cell. Biol., May 1, 2005; 25(9): 3630 - 3638. [Abstract] [Full Text] [PDF]

				I. Grgic, I. Eichler, P. Heinau, H. Si, S. Brakemeier, J. Hoyer, and R. Kohler Selective Blockade of the Intermediate-Conductance Ca2+-Activated K+ Channel Suppresses Proliferation of Microvascular and Macrovascular Endothelial Cells and Angiogenesis In Vivo Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 704 - 709. [Abstract] [Full Text] [PDF]

				A. Sato, K. Terata, H. Miura, K. Toyama, F. R. Loberiza Jr., O. A. Hatoum, T. Saito, I. Sakuma, and D. D. Gutterman Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1633 - H1640. [Abstract] [Full Text] [PDF]

				H. Wulff, H.-G. Knaus, M. Pennington, and K. G. Chandy K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity J. Immunol., July 15, 2004; 173(2): 776 - 786. [Abstract] [Full Text] [PDF]