Published Online
on August 25, 2003

A more recent version of this article appeared on September 2, 2003

This Article 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 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. Related Collections Restenosis

Submitted on January 17, 2003
Revised on April 24, 2003
Accepted on April 25, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: koe{at}zedat.fu-berlin.de.

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:

				X. Long, D. L. Tharp, M. A. Georger, O. J. Slivano, M. Y. Lee, B. R. Wamhoff, D. K. Bowles, and J. M. Miano The Smooth Muscle Cell-restricted KCNMB1 Ion Channel Subunit Is a Direct Transcriptional Target of Serum Response Factor and Myocardin J. Biol. Chem., November 27, 2009; 284(48): 33671 - 33682. [Abstract] [Full Text] [PDF]

				I. Grgic, E. Kiss, B. P. Kaistha, C. Busch, M. Kloss, J. Sautter, A. Muller, A. Kaistha, C. Schmidt, G. Raman, et al. Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels PNAS, August 25, 2009; 106(34): 14518 - 14523. [Abstract] [Full Text] [PDF]

				V. G. Romanenko, K. S. Roser, J. E. Melvin, and T. Begenisich The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels Am J Physiol Cell Physiol, April 1, 2009; 296(4): C878 - C888. [Abstract] [Full Text] [PDF]

				O. Bardou, N. T. N. Trinh, and E. Brochiero Molecular diversity and function of K+ channels in airway and alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, February 1, 2009; 296(2): L145 - L155. [Abstract] [Full Text] [PDF]

				A. Moreno-Dominguez, P. Cidad, E. Miguel-Velado, J. R. Lopez-Lopez, and M. T. Perez-Garcia De novo expression of Kv6.3 contributes to changes in vascular smooth muscle cell excitability in a hypertensive mice strain J. Physiol., February 1, 2009; 587(3): 625 - 640. [Abstract] [Full Text] [PDF]

				L. Garneau, H. Klein, U. Banderali, A. Longpre-Lauzon, L. Parent, and R. Sauve Hydrophobic Interactions as Key Determinants to the KCa3.1 Channel Closed Configuration: AN ANALYSIS OF KCa3.1 MUTANTS CONSTITUTIVELY ACTIVE IN ZERO Ca2+ J. Biol. Chem., January 2, 2009; 284(1): 389 - 403. [Abstract] [Full Text] [PDF]

				N. T. N. Trinh, A. Prive, E. Maille, J. Noel, and E. Brochiero EGF and K+ channel activity control normal and cystic fibrosis bronchial epithelia repair Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L866 - L880. [Abstract] [Full Text] [PDF]

				R. Tao, C.-P. Lau, H.-F. Tse, and G.-R. Li Regulation of cell proliferation by intermediate-conductance Ca2+-activated potassium and volume-sensitive chloride channels in mouse mesenchymal stem cells Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1409 - C1416. [Abstract] [Full Text] [PDF]

				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]

				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]