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Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1.
Pchejetski D., Foussal C., Alfarano C., Lairez O., Calise D., Guilbeau-Frugier C., Schaak S., Seguelas M.-H., Wanecq E., Valet P. et al
European Heart Journal 33, 18 (2012) 2360-9 - http://www.hal.inserm.fr/inserm-00755509
Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1.
Dmitri Pchejetski1, Camille Foussal2, 3, Chiara Alfarano2, 3, Olivier Lairez2, Denis Calise4, Celine Guilbeau-Frugier5, Stéphane Schaak6, Marie-Hélène Seguelas3, Estelle Wanecq2, 3, Philippe Valet2, 3, Angelo Parini2, 3, Oksana Kunduzova () 2, 3
1 :  Department of Surgery and Cancer
Imperial College London
Cyclotron Building Ducane Road London W12 0NN
2 :  I2MC - UPS III - Institut des Maladies Métaboliques et Cardiovasculaires
Université Paul Sabatier (UPS) - Toulouse III
1, avenue Jean Poulhès BP 84225 31432 TOULOUSE CEDEX 4
3 :  I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
INSERM : U1048 – Université Paul Sabatier (UPS) - Toulouse III – Hôpital de Rangueil
1 avenue du Prof Jean Poulhes - BP 84225 - 31432 Toulouse Cedex 4
4 :  Service de Microchirurgie Expérimentale
1, avenue Jean Poulhès BP 84225 31432 TOULOUSE CEDEX 4
5 :  Service d'anatomie pathologique et histologie-cytologie [Rangueil]
CHU Toulouse – Hôpital de Rangueil – Université Paul Sabatier (UPS) - Toulouse III
1, avenue du Professeur Jean Poulhès - TSA 50032 - 31059 Toulouse cedex 9
6 :  MATN - Modélisation de l'Agression Tissulaire et de la Nociception
Université Paul Sabatier (UPS) - Toulouse III – EA 4564
118 route de Narbonne 31062 TOULOUSE CEDEX 9
AIMS: Activation of cardiac fibroblasts and their differentiation into myofibroblasts is a key event in the progression of cardiac fibrosis that leads to end-stage heart failure. Apelin, an adipocyte-derived factor, exhibits a number of cardioprotective properties; however, whether apelin is involved in cardiac fibroblast activation and myofibroblast formation remains unknown. The aim of this study was to determine the effects of apelin in activated cardiac fibroblasts, the potential related mechanisms and impact on cardiac fibrotic remodelling process. METHODS AND RESULTS: In vitro experiments were performed in mouse cardiac fibroblasts obtained from normal and pressure-overload hearts. Pretreatment of naive cardiac fibroblasts with apelin (1-100 nM) inhibited Transforming growth factor-β (TGF-β)-mediated expression of the myofibroblast marker α-smooth muscle actin (α-SMA) and collagen production. Furthermore, apelin decreased the spontaneous collagen production in cardiac fibroblasts isolated from hearts after aortic banding. Knockdown strategy and pharmacological inhibition revealed that prevention of collagen accumulation by apelin was mediated by a reduction in sphingosine kinase 1 (SphK1) activity. In vivo studies using the aortic banding model indicated that pretreatment with apelin attenuated the development of myocardial fibrotic remodelling and inhibited cardiac SphK1 activity and α-SMA expression. Moreover, administration of apelin 2 weeks after aortic banding prevented cardiac remodelling by inhibiting myocyte hypertrophy, cardiac fibrosis, and ventricular dysfunction. CONCLUSION: Our data provide the first evidence that apelin inhibits TGF-β-stimulated activation of cardiac fibroblasts through a SphK1-dependent mechanism. We also demonstrated that the administration of apelin during the phase of reactive fibrosis prevents structural remodelling of the myocardium and ventricular dysfunction. These findings may have important implications for designing future therapies for myocardial performance during fibrotic remodelling, affecting the clinical management of patients with progressive heart failure.
Sciences du Vivant/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire

Articles dans des revues avec comité de lecture
European Heart Journal (Eur Heart J)
Publisher Oxford University Press (OUP): Policy B
ISSN 0195-668X (eISSN : 1522-9645)