Titre
Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Kraler, S.
Auteure/Auteur
Balbi, C.
Auteure/Auteur
Vdovenko, D.
Auteure/Auteur
Lapikova-Bryhinska, T.
Auteure/Auteur
Camici, G.G.
Auteure/Auteur
Liberale, L.
Auteure/Auteur
Bonetti, N.
Auteure/Auteur
Canestro, C.D.
Auteure/Auteur
Burger, F.
Auteure/Auteur
Roth, A.
Auteure/Auteur
Carbone, F.
Auteure/Auteur
Vassalli, G.
Auteure/Auteur
Mach, F.
Auteure/Auteur
Bhasin, S.
Auteure/Auteur
Wenzl, F.A.
Auteure/Auteur
Muller, O.
Auteure/Auteur
Räber, L.
Auteure/Auteur
Matter, C.M.
Auteure/Auteur
Montecucco, F.
Auteure/Auteur
Lüscher, T.F.
Auteure/Auteur
Akhmedov, A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1755-3245
Statut éditorial
Publié
Date de publication
2023-12-30
Volume
119
Numéro
17
Première page
2729
Dernière page/numéro d’article
2742
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing.
In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels.
Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.
In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels.
Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI.
Sujets
PID Serval
serval:BIB_61F93877E926
PMID
Open Access
Oui
Date de création
2023-09-29T13:02:43.155Z
Date de création dans IRIS
2025-05-20T17:01:44Z
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Nom
37742057_BIB_61F93877E926.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
7.27 MB
Format
Adobe PDF
PID Serval
serval:BIB_61F93877E926.P001
URN
urn:nbn:ch:serval-BIB_61F93877E9261
Somme de contrôle
(MD5):5276ee16b743b370c2fc785fa8c7b452