Growth Differentiation Factor 15 (GDF15) Expression in the Heart After Myocardial Infarction and Cardioprotective Effect of Pre-Ischemic rGDF15 Administration

Clinical data consider growth differentiation factor-15 GDF15 as a prognostically unfavourable biomarker in cardiovascular diseases, while experimental studies suggest its cardioprotective potential. This study focuses on the direct cardiac effects of GDF15 during ischemia-reperfusion (I/R) 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 I/R and Sham operations in vivo. Subsequently, we evaluated the cardiac effects of GDF15 both in vivo and ex vivo, administering recombinant GDF15 either before ischemia (preconditioning) or at the onset of reperfusion (postconditioning). We compared infarct sizes and recovery of cardiac contractile parameters between control and rGDF15 treated rats. Contrary to our expectations, I/R did not elevate GDF15 plasma levels compared to Sham-operated rats. However, cardiac expression at both protein and mRNA levels increased in the infarcted zone of the ischemic heart after 24 hours of reperfusion. Notably, preconditioning with rGDF15 exhibited a cardioprotective effect, reducing infarct size both in vivo and ex vivo, while enhancing the recovery of cardiac contractile parameters ex vivo. However, postconditioning with rGDF15 did not alter infarct size or the recovery of contractile parameters either in vivo or ex vivo. These findings reveal, for the first time, that short-term exogenous administration of rGDF15 before ischemia, at physiologically relevant levels, protects the heart against I/R injury in both in vivo and ex vivo settings. The latter situation suggests that rGDF15 can operate independently of the inflammatory, endocrine and nervous systems, presenting GDF15 as a direct and potent cardioprotective properties against ischemia-reperfusion injury.