Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Department of Surgery and Cancer,  Imperial College London, London,  UK.
Dmitri
D
Pchejetski
Camille
C
Foussal
Chiara
C
Alfarano
Olivier
O
Lairez
Denis
D
Calise
Celine
C
Guilbeau-Frugier
Stéphane
S
Schaak
Marie-Hélène
MH
Seguelas
Estelle
E
Wanecq
Philippe
P
Valet
Angelo
A
Parini
Oksana
O
Kunduzova
D055372:AMP-Activated Protein Kinases / Q000494:pharmacology; D054392:Adipokines; D000818:Animals; D000073861:Apelin; D003094:Collagen / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000502:physiology; D000099157:Sphingosine Kinase
D055372:AMP-Activated Protein Kinases; D054392:Adipokines; D000073861:Apelin; D003094:Collagen; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D016212:Transforming Growth Factor beta; D000099157:Sphingosine Kinase; C402826:Apln protein, mouse