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 journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)1275-1284
Number of pages10
JournalCirculation Research
Volume106
Issue number7
DOIs
Publication statusPublished - Apr 2010

Keywords

  • Angiogenesis
  • Apoptosis
  • Gene therapy
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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