doi: 10.1161/CIRCULATIONAHA.108.190524
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(Circulation. 2008;118:979-980.)
© 2008 American Heart Association, Inc.
Clinical Summaries
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
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Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve |
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Repolarization reserve is an important determinant of the response to contexts involving action potential prolongation, including potassium channel–blocking drugs (both antiarrhythmic agents and compounds with collateral effects on potassium channels), bradycardic drugs, and electrolyte disturbances like hypokalemia and hypomagnesemia. Repolarization reserve is generally attributed to functionally based compensatory increases in potassium currents in response to action potential duration–prolonging tendencies that minimize the resulting action potential prolongation. The possibility that sustained action potential prolongation by potassium channel inhibition may induce remodeling of ion current expression has not been tested. Accordingly, we assessed the effects of sustained rapid delayed-rectifier potassium current (IKr) inhibition with dofetilide on various cardiac ionic currents in isolated paced/cultured dog cardiomyocytes. Sustained dofetilide exposure led to abbreviated action potential duration and increased repolarization reserve (reduced action potential duration–prolonging response to IKr blockade), along with increased slow delayed-rectifier current (IKs) density. A variety of other currents remained unchanged. The mRNA expression of IKs subunits was unchanged, but their protein expression was increased, suggesting posttranscriptional regulation. We quantified the muscle-specific microRNA subtypes miR-133a and miR-133b, which can posttranscriptionally repress protein expression of the IKs
-subunit KvLQT1. Expression levels of miR-133a and miR-133b were decreased in cells cultured in dofetilide, possibly accounting for KvLQT1 protein upregulation. We conclude that chronic action potential prolongation can cause compensatory upregulation of potassium currents, possibly mediated (at least in part) by microRNA changes, adding the regulation of ion channel expression to the potential mechanisms governing repolarization reserve. Function and
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