New Cardiomyokine Reduces Myocardial Ischemia/Reperfusion Injury by PI3K-AKT Pathway Via a Putative KDEL-Receptor Binding

J Am Heart Assoc. 2021 Jan 5;10(1):e019685. doi: 10.1161/JAHA.120.019685. Epub 2020 Dec 29.

Abstract

Background CDNF (cerebral dopamine neurotrophic factor) belongs to a new family of neurotrophic factors that exert systemic beneficial effects beyond the brain. Little is known about the role of CDNF in the cardiac context. Herein we investigated the effects of CDNF under endoplasmic reticulum-stress conditions using cardiomyocytes (humans and mice) and isolated rat hearts, as well as in rats subjected to ischemia/reperfusion (I/R). Methods and Results We showed that CDNF is secreted by cardiomyocytes stressed by thapsigargin and by isolated hearts subjected to I/R. Recombinant CDNF (exoCDNF) protected human and mouse cardiomyocytes against endoplasmic reticulum stress and restored the calcium transient. In isolated hearts subjected to I/R, exoCDNF avoided mitochondrial impairment and reduced the infarct area to 19% when administered before ischemia and to 25% when administered at the beginning of reperfusion, compared with an infarct area of 42% in the untreated I/R group. This protection was completely abrogated by AKT (protein kinase B) inhibitor. Heptapeptides containing the KDEL sequence, which binds to the KDEL-R (KDEL receptor), abolished exoCDNF beneficial effects, suggesting the participation of KDEL-R in this cardioprotection. CDNF administered intraperitoneally to rats decreased the infarct area in an in vivo model of I/R (from an infarct area of ≈44% in the I/R group to an infarct area of ≈27%). Moreover, a shorter version of CDNF, which lacks the last 4 residues (CDNF-ΔKTEL) and thus allows CDNF binding to KDEL-R, presented no cardioprotective activity in isolated hearts. Conclusions This is the first study to propose CDNF as a new cardiomyokine that induces cardioprotection via KDEL receptor binding and PI3K/AKT activation.

Keywords: KDEL‐receptor; PI3K‐AKT pathway; cardioprotection; cerebral dopamine neurotrophic factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / metabolism
  • Cardiotonic Agents / pharmacology
  • Endoplasmic Reticulum Stress / drug effects*
  • Humans
  • Mice
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / prevention & control
  • Myocytes, Cardiac* / drug effects
  • Myocytes, Cardiac* / metabolism
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptors, Peptide / metabolism*
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects

Substances

  • CDNF protein, human
  • Cardiotonic Agents
  • KDEL receptor
  • Nerve Growth Factors
  • Receptors, Peptide
  • Recombinant Proteins
  • Proto-Oncogene Proteins c-akt