Overexpression of cyclic adenosine monophosphate effluent protein MRP4 induces an altered response to β-adrenergic stimulation in the senescent rat heart.
BACKGROUND
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.


METHODS
The β-adrenergic responses to isoproterenol were investigated in vivo (stress echocardiography) and in vitro (isolated cardiomyocyte by Ionoptix 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.


RESULTS
The positive inotropic effect of isoproterenol was reduced in senescent rats in vivo (left ventricular shortening fraction 120 ± 16% vs. 158 ± 20%, P < 0.001, n = 16 rats) and in vitro (sarcomere shortening 129 ± 37% vs. 148 ± 35%, P = 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 (P = 0.012, n = 8 rats per group). In senescent rats, inhibition of MRP4 by MK571 restored the positive inotropic effect of isoproterenol in vivo (143 ± 11%, n = 8 rats). In vitro in senescent cardiomyocytes pretreated with MK571, both sarcomere shortening (161 ± 45% vs. 129 ± 37%, P = 0.007, n = 41 cells per group) and calcium transient amplitude (132 ± 25% vs. 113 ± 27%, P = 0.007) increased significantly.


CONCLUSIONS
MRP4 overexpression contributes to the reduction of the positive inotropic response to β-adrenoceptor stimulation in the senescent heart.
From the Sorbonne Universités UPMC Univ Paris 06, UMR INSERM-UPMC 1166, Paris, France (A.C., S.F., C.J., F.A., N.M., J.-S.H., B.R., J.A.); Department of Anesthesiology and Critical Care Medicine (A.C., J.A.), Department of Emergency Medicine and Surgery (N.N., B.R.), and Department of Pharmacology (J.-S.H.), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Reims Champagne-Ardenne and Department of Anesthesiology and Critical Care Medicine, Robert Debré Hospital, Reims, France (A.C.); Wuhan University, Wuhan, The People's Republic of China (C.J.); UMR INSERM 902 Université Evry Val d'Essone, Evry, France (S.B.); and Université Paris-Descartes, Paris, France (S.B.).
Aude
A
Carillion
Sarah
S
Feldman
Cheng
C
Jiang
Fabrice
F
Atassi
Na
N
Na
Nathalie
N
Mougenot
Sophie
S
Besse
Jean-Sébastien
JS
Hulot
Bruno
B
Riou
Julien
J
Amour
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000375:Aging / Q000502:physiology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D025401:Echocardiography, Stress; D006321:Heart / Q000187:drug effects* / Q000254:growth & development; D007545:Isoproterenol / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D002118:Calcium; D007545:Isoproterenol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C489542:Abcc4 protein, rat; C059141:verlukast