Cerebral dopamine neurotrophic factor (CDNF) reduces myocardial ischemia/reperfusion injuries by the activation of PI3K-AKT via KDEL-receptor binding

CDNF (Cerebral Dopamine Neurotrophic Factor) belongs to a new family of NF, which presents several beneficial activities beyond the brain. Little is known about CDNF in the cardiac context. Herein we investigate CDNF effects in cardiomyocytes under endoplasmic reticulum (ER)-stress and in whole rat hearts subjected to ischemia/reperfusion (I/R). We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. CDNF protects human and mouse cardiomyocytes against ER-stress by restoring the calcium transient, and isolated heart against I/R injuries by reducing the infarct area and avoiding mitochondrial impairment. This protection is abrogated by wortmannin (PI3K- inhibitor) or by heptapeptides containing KDEL sequence, which block KDEL-receptor. These data suggest that CDNF induces cardioprotection via KDEL receptor binding and PI3K/AKT activation. This is the first study to propose CDNF as a cardiomyokine and to unravel the receptor and signaling pathway for this interesting family of NF.