title: Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization.
abstract: OBJECTIVE
  Ventricular remodelling following myocardial infarction progressively leads to loss of contractile capacity and heart failure. Although calcineurin promotes maladaptive cardiac hypertrophy, we recently showed that the calcineurin splicing variant, CnAβ1, has beneficial effects on the infarcted heart. However, whether this variant limits necrosis or improves remodelling is still unknown, precluding translation to the clinical arena. Here, we explored the effects and therapeutic potential of CnAβ1 overexpression post-infarction.
  
  
  RESULTS
  Double transgenic mice with inducible cardiomyocyte-specific overexpression of CnAβ1 underwent left coronary artery ligation followed by reperfusion. Echocardiographic analysis showed depressed cardiac function in all infarcted mice 3 days post-infarction. Induction of CnAβ1 overexpression 1 week after infarction improved function and reduced ventricular dilatation. CnAβ1-overexpressing mice showed shorter, thicker scars, and reduced infarct expansion, accompanied by reduced myocardial remodelling. CnAβ1 induced vascular endothelial growth factor (VEGF) expression in cardiomyocytes, which resulted in increased infarct vascularization. This paracrine angiogenic effect of CnAβ1 was mediated by activation of the Akt/mammalian target of rapamycin pathway and VEGF.
  
  
  CONCLUSIONS
  Our results indicate that CnAβ1 exerts beneficial effects on the infarcted heart by promoting infarct vascularization and preventing infarct expansion. These findings emphasize the translational potential of CnAβ1 for gene-based therapies.
authors.affiliation: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Marina M
authors.initials: MM
authors.lastname: López-Olañeta
authors.affiliation: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Villalba
authors.affiliation: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Gómez-Salinero
authors.affiliation: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: National Institute for Medical Research, Medical Research Council, London, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Breckenridge
authors.affiliation: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Ortiz-Sánchez
authors.affiliation: Servicio de Cardiología, Hospital Puerta de Hierro de Majadahonda, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: García-Pavía
authors.affiliation: Epidemiology, Atherothrombosis and Imaging Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Cardiovascular Institute, Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Ibáñez
authors.affiliation: Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, Madrid 28029, Spain National Heart and Lung Institute, Imperial College London, London, UK elara@cnic.es.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lara-Pezzi
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D018919:Neovascularization, Physiologic; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D012326:RNA Splicing; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse
keywords: Akt; Calcineurin; Cardiac remodelling; CnAβ1; Myocardial infarction