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*
*,1
* Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee UK; and
Division of Cell Biology and Immunology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee, UK
1Correspondence: Maternal and Child Health Sciences, Ninewells Hospital & Medical School, University of Dundee, Dundee, DD1 9SY Scotland, UK. E-mail: a.jovanovic{at}dundee.ac.uk
ATP-sensitive K+ (KATP) channels are present in the sarcolemma of cardiac myocytes where they link membrane excitability with the cellular bioenergetic state. These channels are in vivo composed of Kir6.2, a pore-forming subunit, SUR2A, a regulatory subunit, and at least four accessory proteins. In the present study, real-time RT-PCR has demonstrated that of all six sarcolemmal KATP channel-forming proteins, SUR2A was probably the least expressed protein. We have generated mice where the SUR2A was under the control of a cytomegalovirus promoter, a promoter that is more efficient than the native promoter. These mice had an increase in SUR2A mRNA/protein levels in the heart whereas levels of mRNAs of other channel-forming proteins were not affected at all. Imunoprecipitation/Western blot and patch clamp electrophysiology has shown an increase in KATP channel numbers in the sarcolemma of transgenic mice. Cardiomyocytes from transgenic mice responded to hypoxia with shortening of action membrane potential and were significantly more resistant to this insult than cardiomyocytes from the wild-type. The size of myocardial infarction in response to ischemia-reperfusion was much smaller in hearts from transgenic mice compared to those in wild-type. We conclude that overexpression of SUR2A generates cardiac phenotype resistant to hypoxia/ischemia/reperfusion injury due at least in part to increase in levels of sarcolemmal KATP channels.—Du, Q., Jovanovi, S., Clelland, A., Sukhodub, A., Budas, G., Phelan, K., Murray-Tait, V., Malone, L., Jovanovi, A. Overexpression of sur2a generates cardiac phenotype resistant to ischemia.
Key Words: SUR2A • KATP channel • cardioprotection • hypoxia • heart
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