This Article Full Text Full Text (PDF) All Versions of this Article: 106/12/1556    most recent 01.CIR.0000028424.02525.AEv1 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 Lawrence, K.M. Articles by Latchman, D.S. Search for Related Content PubMed PubMed Citation Articles by Lawrence, K.M. Articles by Latchman, D.S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Cell signalling/signal transduction Gene regulation Growth factors/cytokines Ion channels/membrane transport

(Circulation. 2002;106:1556.)
© 2002 American Heart Association, Inc.

Basic Science Reports

K_ATP Channel Gene Expression Is Induced by Urocortin and Mediates Its Cardioprotective Effect

K.M. Lawrence, PhD; A. Chanalaris, MSc; T. Scarabelli, MD; M. Hubank, PhD; E. Pasini, MD; P.A. Townsend, PhD; L. Comini, MSc; R. Ferrari, MD; A. Tinker, PhD; A. Stephanou, PhD; R.A. Knight, MD, PhD; D.S. Latchman, PhD, DSc

From the Medical Molecular Biology Unit (K.M.L., A.C., T.S., M.H., A.S., D.S.L.), Institute of Child Health, University College London, London, England; Cardiovascular Pathophysiology Research Centre (E.P., L.C., R.F.), S. Maugeri Foundation IRCCS, University of Ferrara, Italy; Centre for Clinical Pharmacology (A.T.), Department of Medicine, University College London, England; and National Heart and Lung Institute (R.A.K.), Royal Brompton Hospital, London, England.

Correspondence to D.S. Latchman, PhD, DSc, Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. E-mail d.latchman@ ich.ucl.ac.uk

Background— Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.

Methods and Results— We have analyzed global changes in gene expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K_ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.

Conclusions— This is, to our knowledge, the first report of the altered expression of a K_ATP channel subunit induced by a cardioprotective agent and demonstrates that K_ATP channel opening is essential for the effect of this novel cardioprotective agent.

Key Words: potassium channel • urocortin • ischemia • reperfusion

This article has been cited by other articles:

				P. A. Townsend, S. M. Davidson, S. J. Clarke, I. Khaliulin, C. J. Carroll, T. M. Scarabelli, R. A. Knight, A. Stephanou, D. S. Latchman, and A. P. Halestrap Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H928 - H938. [Abstract] [Full Text] [PDF]

				T. M. Scarabelli, E. Pasini, G. Ferrari, M. Ferrari, A. Stephanou, K. Lawrence, P. Townsend, C. Chen-Scarabelli, G. Gitti, L. Saravolatz, et al. Warm blood cardioplegic arrest induces mitochondrial-mediated cardiomyocyte apoptosis associated with increased urocortin expression in viable cells J. Thorac. Cardiovasc. Surg., September 1, 2004; 128(3): 364 - 371. [Abstract] [Full Text] [PDF]

				K. Takahashi, K. Totsune, O. Murakami, M. Saruta, M. Nakabayashi, T. Suzuki, H. Sasano, and S. Shibahara Expression of Urocortin III/Stresscopin in Human Heart and Kidney J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1897 - 1903. [Abstract] [Full Text] [PDF]

				B. K. Brar, A. K. Jonassen, E. M. Egorina, A. Chen, A. Negro, M. H. Perrin, O. D. Mjos, D. S. Latchman, K.-F. Lee, and W. Vale Urocortin-II and Urocortin-III Are Cardioprotective against Ischemia Reperfusion Injury: An Essential Endogenous Cardioprotective Role for Corticotropin Releasing Factor Receptor Type 2 in the Murine Heart Endocrinology, January 1, 2004; 145(1): 24 - 35. [Abstract] [Full Text] [PDF]