Nerve growth factor promotes cardiac repair following myocardial infarction

Marco Meloni, Andrea Caporali, Gallia Graiani, Costanza Lagrasta, Rajesh Katare, Sophie Van Linthout, Frank Spillmann, Ilaria Campesi, Paolo Madeddu, Federico Quaini, Costanza Emanueli

Research output: Contribution to journalArticle (Academic Journal)

124 Citations (Scopus)

Abstract

RATIONALE: Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated.

OBJECTIVE: To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI).

METHODS AND RESULTS: Immunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kit(pos) progenitor cells in NGF-engineered hearts.

CONCLUSIONS: NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.

Translated title of the contributionNerve growth factor promotes cardiac repair following myocardial infarction
Original languageEnglish
Pages (from-to)1275 - 1284
Number of pages12
JournalCirculation Research
Volume106
Issue number7
DOIs
Publication statusPublished - 16 Apr 2010

Bibliographical note

Publisher: American Heart Association

Keywords

  • Aged
  • Animals
  • Apoptosis
  • Autopsy
  • Case-Control Studies
  • Cells, Cultured
  • Coronary Circulation
  • Disease Models, Animal
  • Endothelial Cells
  • Female
  • Forkhead Transcription Factors
  • Genetic Therapy
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Myocardial Infarction
  • Myocardium
  • Neovascularization, Physiologic
  • Nerve Growth Factor
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-kit
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Receptor, trkA
  • Recombinant Proteins
  • Regeneration
  • Signal Transduction
  • Stem Cell Factor
  • Stem Cells
  • Time Factors
  • Transfection
  • Ventricular Function, Left

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    Meloni, M., Caporali, A., Graiani, G., Lagrasta, C., Katare, R., Van Linthout, S., Spillmann, F., Campesi, I., Madeddu, P., Quaini, F., & Emanueli, C. (2010). Nerve growth factor promotes cardiac repair following myocardial infarction. Circulation Research, 106(7), 1275 - 1284. https://doi.org/10.1161/CIRCRESAHA.109.210088