Abstract
The NCX1 (sodium-calcium exchanger) is up-regulated in human heart failure and in many animal models of heart failure. The potential benefits and risks of therapeutically blocking NCX1 in heart failure and during ischemia-reperfusion are being actively investigated. In this study, we demonstrate that prolonged administration of the NCX1 inhibitor KB-R7943 resulted in the up-regulation of Ncx1 gene expression in both isolated adult cardiomyocytes and intact mouse hearts. Ncx1 up-regulation is mediated by the activation of p38. Importantly, p38 is not activated by KB-R7943 treatment in heart tubes from Ncx1(-/-) mice at 9.5 days postcoitum but is activated in heart tubes from Ncx1(+/+) mice. p38 activation does not appear to be in response to changes in cytosolic calcium concentration, [Ca(2+)](i). Interestingly, chronic KB-R7943 treatment in mice leads to the formation of an NCX1-p38 complex. Our study demonstrates for the first time that the electrogenic sarcolemma membrane cardiac NCX1 can act as a regulator of "activity-dependent signal transduction" leading to changes in gene expression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic beta-Antagonists / administration & dosage
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Adrenergic beta-Antagonists / pharmacology
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Animals
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Anti-Arrhythmia Agents / administration & dosage
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Anti-Arrhythmia Agents / pharmacology
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Calcium Channel Blockers / administration & dosage
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Calcium Channel Blockers / pharmacology
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Calcium Channels, L-Type / metabolism
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Cats
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Enzyme Activation / drug effects
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Heart / drug effects*
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Mice
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Myocardium / metabolism*
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Receptors, Adrenergic, beta / metabolism
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Sodium-Calcium Exchanger / genetics*
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Sodium-Calcium Exchanger / metabolism
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Sodium-Hydrogen Exchangers / antagonists & inhibitors
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Thiourea / administration & dosage
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Thiourea / analogs & derivatives*
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Thiourea / pharmacology
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Time Factors
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Up-Regulation / drug effects*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
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Adrenergic beta-Antagonists
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Anti-Arrhythmia Agents
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Calcium Channel Blockers
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Calcium Channels, L-Type
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Receptors, Adrenergic, beta
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Sodium-Calcium Exchanger
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Sodium-Hydrogen Exchangers
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sodium-calcium exchanger 1
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p38 Mitogen-Activated Protein Kinases
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Thiourea