Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.

Kraler, Simon; Balbi, Carolina; Vdovenko, Daria; Lapikova-Bryhinska, Tetiana; Camici, Giovanni G; Liberale, Luca; Bonetti, Nicole; Canestro, Candela Diaz; Burger, Fabienne; Roth, Aline; Carbone, Federico; Vassalli, Giuseppe; Mach, François; Bhasin, Shalender; Wenzl, Florian A; Muller, Olivier; Räber, Lorenz; Matter, Christian M; Montecucco, Fabrizio; Lüscher, Thomas F; ... (2023). Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans. Cardiovascular research, 119(17), pp. 2729-2742. Oxford University Press 10.1093/cvr/cvad153

[img]
Preview
Text
cvad153.pdf - Accepted Version
Available under License Publisher holds Copyright.

Download (2MB) | Preview

AIMS

The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a TGF-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.

METHODS AND RESULTS

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 (rGDF11) delivery (0.1 mg/kg BW 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 a possible indirect effect. Finally, by harnessing a highly-specific and validated LC-MS/MS 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.

CONCLUSION

Our data challenge the initially reported rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Our results suggest that persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes following acute MI.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology

UniBE Contributor:

Räber, Lorenz

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0008-6363

Publisher:

Oxford University Press

Language:

English

Submitter:

Pubmed Import

Date Deposited:

25 Sep 2023 09:45

Last Modified:

24 Sep 2024 00:25

Publisher DOI:

10.1093/cvr/cvad153

PubMed ID:

37742057

BORIS DOI:

10.48350/186551

URI:

https://boris.unibe.ch/id/eprint/186551

Actions (login required)

Edit item Edit item
Provide Feedback