Overexpression of Cyclic Adenosine Monophosphate Effluent Protein MRP4 Induces an Altered Response to β-Adrenergic Stimulation in the Senescent Rat Heart. (February 2015)

• Record Type: Journal Article
• Authors: Carillion, Aude; Feldman, Sarah; Jiang, Cheng; Atassi, Fabrice; Na, Na; Mougenot, Nathalie; Besse, Sophie; Hulot, Jean-Sébastien; Riou, Bruno; Amour, Julien
• Is Part Of: Anesthesiology. Volume 122:Number 2(2015)
• Publication Date: 2015-02
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000526
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>In the senescent heart, the positive inotropic response to β-adrenoceptor stimulation is reduced, partly by dysregulation of β1- and β3-adrenoceptors. The multidrug resistance protein 4 (MRP4) takes part in the control of intracellular cyclic adenosine monophosphate concentration by controlling its efflux but the role of MRP4 in the β-adrenergic dysfunction of the senescent heart remains unknown.</p> </sec> <sec> <title>Methods:</title> <p>The β-adrenergic responses to isoproterenol were investigated <italic>in vivo</italic> (stress echocardiography) and <italic>in vitro</italic> (isolated cardiomyocyte by Ionoptix<sup>®</sup> with sarcomere shortening and calcium transient) in young (3 months old) and senescent (24 months old) rats pretreated or not with MK571, a specific MRP4 inhibitor. MRP4 was quantified in left ventricular homogenates by Western blotting. Data are mean ± SD expressed as percent of baseline value.</p> </sec> <sec> <title>Results:</title> <p>The positive inotropic effect of isoproterenol was reduced in senescent rats <italic>in vivo</italic> (left ventricular shortening fraction 120 ± 16% <italic>vs.</italic> 158 ± 20%, <italic>P</italic> < 0.001, n = 16 rats) and <italic>in vitro</italic> (sarcomere shortening 129 ± 37% <italic>vs.</italic> 148 ± 35%, <italic>P</italic> = 0.004, n = 41 or 43 cells) as compared to young rats. MRP4 expression increased 3.6-fold in senescent compared to young rat myocardium (<italic>P</italic> = 0.012, n = 8 rats per group). In senescent rats, inhibition of MRP4 by MK571 restored the positive inotropic effect of isoproterenol <italic>in vivo</italic> (143 ± 11%, n = 8 rats). <italic>In vitro</italic> in senescent cardiomyocytes pretreated with MK571, both sarcomere shortening (161 ± 45% <italic>vs.</italic> 129 ± 37%, <italic>P</italic> = 0.007, n = 41 cells per group) and calcium transient amplitude (132 ± 25% <italic>vs.</italic> 113 ± 27%, <italic>P</italic> = 0.007) increased significantly.</p> </sec> <sec> <title>Conclusion:</title> <p>MRP4 overexpression contributes to the reduction of the positive inotropic response to β-adrenoceptor stimulation in the senescent heart.</p> </sec> </abstract>