Growth Differentiation Factor 15 (Gdf15) is Expressed in the Heart after Myocardial Infarction, But Exogenous Rgdf15 Only Exerts Pre-Ischemic Cardioprotection

Abstract

Aims: We aimed to clarify the kinetics of growth differentiation factor 15 (GDF15) production during myocardial ischemia-reperfusion (I-R) injury and to evaluate the pre or post-conditioning direct cardioprotective effects of exogenous GDF15 administration, at concentrations found in patients with high cardiovascular risk (above 2,000 ng/L). 

Main methods: Wistar male rats were used for all experiments, circulating levels and heart tissue expression of GDF15 were evaluated in vivo in I/R and Sham operated rats. GDF15 cardiac effects were assessed both in vivo and ex vivo with recombinant GDF15 administered either before ischemia (preconditioning) or at the onset of reperfusion (postconditioning). Infarct sizes and cardiac contractile parameters recovery were evaluated. 

Key findings: I/R did not increase GDF15 plasma levels as compared to Sham operated rats, however its cardiac expression was increased at both protein and mRNA levels in the infarcted zone of the ischemic heart after 24 h of reperfusion. rGDF15 preconditioning protected the heart from I/R, lowering infarct size in vivo and ex vivo and improving cardiac contractile parameters recovery ex vivo. However, rGDF15 postconditioning did neither modify the infarct size in vivo and ex vivo, nor contractile parameters’ recovery ex vivo. 

Significance: These results demonstrate for the first time that exogenous preischemic short-term administration of rGDF15, at relevant pathophysiologic levels, protected the heart towards I/R injuries in vivo and ex vivo. The latter situation suggests that rGDF15 can act independently of the inflammatory, endocrine and nervous systems, suggesting that GDF15 exerts direct cardioprotective properties.

Note:
Funding Declaration: This study has been supported by funding from the French Ministry of Research, from the Regional Council of Burgundy, from the Association Bourguignonne de Cardiologie, and from the Regional University Hospital and Faculty of Health Sciences and from the ANR (SMOG15-CE17-009-01).

Conflict of Interests: The authors declare no conflict of interest.

Ethical Approval: The investigation was approved by the local ethics committee (Comité d’Ethique de l’Expérimentation Animale Université Bourgogne Franche-Comté, Dijon, France, protocol agreement number: APAFIS#16546-2018082915228167v4) and carried out in accordance with Directive 2010/63/EU of the European Parliament and to the Guide for the Care of Laboratory Animals published by the US Nation Institutes of Health (NIH Publication No. 85-23, revised 1996).

Keywords: GDF-15, Ischemia-reperfusion injury, Heart, preconditioning, Cardioprotection