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Gene Transfer for Ischemic Heart Failure in a Preclinical Model
Published on: May 15, 2011
Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective
Geoffrey Dogon1, Eve Rigal1, Eliot Potel1
1Research Team: Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Faculty of Health Sciences, University of Burgundy, 7 Bd Jeanne d'Arc, 21000, Dijon, France.
Insights
Growth/differentiation factor-15 (GDF15) preconditioning protects the heart from ischemia-reperfusion injury. This study shows GDF15 reduces infarct size and improves cardiac function, suggesting direct cardioprotective effects.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Regenerative Medicine
Background:
- Growth/differentiation factor-15 (GDF15) has conflicting roles in cardiovascular disease, with clinical data suggesting poor prognosis but experimental data indicating cardioprotection.
- Understanding GDF15's direct cardiac effects during ischemia-reperfusion injury is crucial for evaluating its therapeutic potential.
Purpose of the Study:
- To investigate the direct cardiac effects of GDF15 during ischemia-reperfusion injury in Wistar rats.
- To evaluate GDF15's cardioprotective potential when administered before ischemia (preconditioning) or at reperfusion (postconditioning).
Main Methods:
- Assessed GDF15 levels in plasma and heart tissue after ischemia-reperfusion and sham operations in Wistar rats.
- Administered recombinant GDF15 (rGDF15) in vivo and ex vivo before ischemia or at reperfusion.
- Quantified infarct size and cardiac contractile recovery in control and rGDF15-treated groups.
Main Results:
- Ischemia-reperfusion did not alter circulating GDF15 levels but increased cardiac GDF15 expression.
- Preconditioning with rGDF15 significantly reduced infarct size in vivo and ex vivo.
- rGDF15 preconditioning enhanced ex vivo cardiac contractile recovery, while postconditioning showed no significant effects.
Conclusions:
- Exogenous rGDF15 administration before ischemia provides significant cardioprotection against ischemia-reperfusion injury.
- rGDF15 demonstrates direct cardioprotective properties, independent of systemic factors, suggesting therapeutic potential.
Abstract:
Growth/differentiation factor-15 (GDF15) is considered an unfavourable prognostic biomarker for cardiovascular disease in clinical data, while experimental studies suggest it has cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia-reperfusion injury in Wistar male rats, employing concentrations relevant to patients at high cardiovascular risk. Initially, we examined circulating levels and heart tissue expression of GDF15 in rats subjected to ischemia-reperfusion and sham operations in vivo. We then evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before 30 min of ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct size and cardiac contractile recovery between control and rGDF15-treated rats. Contrary to our expectations, ischemia-reperfusion did not increase GDF15 plasma levels compared to sham-operated rats. However, cardiac protein and mRNA expression increased in the infarcted zone of the ischemic heart after 24 h of reperfusion. Notably, preconditioning with rGDF15 had a cardioprotective effect, reducing infarct size both in vivo (65 ± 5% in control vs. 42 ± 6% in rGDF15 groups) and ex vivo (60 ± 4% in control vs. 45 ± 4% in rGDF15 groups), while enhancing cardiac contractile recovery ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters in vivo or ex vivo. These novel findings reveal that the short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against ischemia-reperfusion injury in both in vivo and ex vivo settings. The ex vivo results indicate that rGDF15 operates independently of the inflammatory, endocrine and nervous systems, suggesting direct and potent cardioprotective properties against ischemia-reperfusion injury.
