Proximal and distant expression of growth differentiation factor 15 (GDF15) correlate with neurological deficit following experimental ischemic stroke

PLoS One. 2024 Jul 15;19(7):e0307105. doi: 10.1371/journal.pone.0307105. eCollection 2024.

Abstract

Background and purpose: Growth differentiation factor 15 (GDF15) has emerged as a promising biomarker in cerebro-cardiovascular disease, particularly in acute and chronic inflammatory stress situations. However, understanding the origins, targets and functions of GDF15 in clinical situations, such as ischemic stroke, remains a complex challenge. This study aims to assess the sources of GDF15 production following an experimental ischemic stroke.

Methods: Adult male Wistar rats underwent cerebral embolization through microspheres injection into the left or right internal carotid artery. Two hours post-surgery, GDF15 expression was analyzed in the brain, blood, lungs, liver and heart using quantitative RT-PCR and Western blotting.

Results: Stroke model induced large cerebral infarcts accompanied by severe neurological deficits. GDF15 gene expression exhibited a substantial increase in the ipsilateral cortex and cerebellum, with a lesser extent in the contralateral cortex. Regarding GDF15 protein expression, proGDF15 levels were elevated in the 3 aforementioned organs mentioned and the heart. However, the mature form of GDF15 was exclusively present and increased in the heart. Finally, the expression of GDF15 expression was correlated with the neurological deficit score.

Conclusions: Our findings suggest that both the GDF15 gene and pro-protein are expressed in the ischemic brain after a stroke, while only its mature form is expressed remotely in in the heart. The impact of increased GDF15 in the heart following a stroke remains to be established. This is particularly relevant in understanding its relationships with poor neurological outcomes, determining whether it may contribute to stroke-induced cardiac dysfunction.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Growth Differentiation Factor 15* / genetics
  • Growth Differentiation Factor 15* / metabolism
  • Ischemic Stroke / complications
  • Ischemic Stroke / genetics
  • Ischemic Stroke / metabolism
  • Male
  • Myocardium / metabolism
  • Myocardium / pathology
  • Rats
  • Rats, Wistar*
  • Stroke / genetics
  • Stroke / metabolism

Substances

  • Growth Differentiation Factor 15
  • Gdf15 protein, rat

Grants and funding

This study has been supported by funding from the French Ministry of Research (CV), from the Regional Council of Burgundy (CV, YB), from the Association Bourguignonne de Cardiologie, and from the Regional University Hospital (YB, AM) and Faculty of Health Sciences (ER, GD) and from the ANR (SMOG15-CE17-009-01, YB, CV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.