Published Online
on August 26, 2002

A more recent version of this article appeared on September 17, 2002

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Submitted on May 1, 2002
Revised on June 16, 2002
Accepted on June 16, 2002

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. Towsend PhD, L. Comini MSc, R. Ferrari MD, A. Tinker PhD, A. Stephanou PhD, R. A. Knight MD, PhD, and 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.

^* To whom correspondence should be addressed. E-mail: d.latchman{at}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

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