Critical role of phosphodiesterase 2A in mouse congenital heart defects

Maria Rita Assenza, Federica Barbagallo, Florencia Barrios, Marisa Cornacchione, Federica Campolo, Elisabetta Vivarelli, Daniele Gianfrilli, Luigi Auletta, Andrea Soricelli, Andrea M. Isidori, Andrea Lenzi, Manuela Pellegrini, Fabio Naro

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims Phosphodiesterase 2 A (Pde2A), a cAMP-hydrolysing enzyme, is essential for mouse development; however, the cause of Pde2A knockout embryonic lethality is unknown. To understand whether Pde2A plays a role in cardiac development, hearts of Pde2A deficient embryos were analysed at different stage of development. Methods and results At the stage of four chambers, Pde2A deficient hearts were enlarged compared to the hearts of Pde2A heterozygous and wild-Type. Pde2A knockout embryos revealed cardiac defects such as absence of atrial trabeculation, interventricular septum (IVS) defects, hypertrabeculation and thinning of the myocardial wall and in rare cases they had overriding aorta and valves defects. E14.5 Pde2A knockouts showed reduced cardiomyocyte proliferation and increased apoptosis in the IVS and increased proliferation in the ventricular trabeculae. Analyses of E9.5 Pde2A knockout embryos revealed defects in cardiac progenitor and neural crest markers, increase of Islet1 positive and AP2 positive apoptotic cells. The expression of early cTnI and late Mef2c cardiomyocyte differentiation markers was strongly reduced in Pde2A knockout hearts. The master transcription factors of cardiac development, Tbx, were down-regulated in E14.5 Pde2A knockout hearts. Absence of Pde2A caused an increase of intracellular cAMP level, followed by an up-regulation of the inducible cAMP early repressor, Icer in fetal hearts. In vitro experiments on wild-Type fetal cardiomyocytes showed that Tbx gene expression is down-regulated by cAMP inducers. Furthermore, Pde2A inhibition in vivo recapitulated the heart defects observed in Pde2A knockout embryos, affecting cardiac progenitor cells. Interestingly, the expression of Pde2A itself was dramatically affected by Pde2A inhibition, suggesting a potential autoregulatory loop. Conclusions We demonstrated for the first time a direct relationship between Pde2A impairment and the onset of mouse congenital heart defects, highlighting a novel role for cAMP in cardiac development regulation.

Original languageEnglish
Pages (from-to)830-845
Number of pages16
JournalCardiovascular Research
Volume114
Issue number6
DOIs
Publication statusPublished - May 1 2018

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Type 2 Cyclic Nucleotide Phosphodiesterases
Congenital Heart Defects
Embryonic Structures
Cardiac Myocytes
2'-phosphodiesterase

Keywords

  • CHD
  • Icer
  • Pde2A
  • Tbx genes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Assenza, M. R., Barbagallo, F., Barrios, F., Cornacchione, M., Campolo, F., Vivarelli, E., ... Naro, F. (2018). Critical role of phosphodiesterase 2A in mouse congenital heart defects. Cardiovascular Research, 114(6), 830-845. https://doi.org/10.1093/cvr/cvy030

Critical role of phosphodiesterase 2A in mouse congenital heart defects. / Assenza, Maria Rita; Barbagallo, Federica; Barrios, Florencia; Cornacchione, Marisa; Campolo, Federica; Vivarelli, Elisabetta; Gianfrilli, Daniele; Auletta, Luigi; Soricelli, Andrea; Isidori, Andrea M.; Lenzi, Andrea; Pellegrini, Manuela; Naro, Fabio.

In: Cardiovascular Research, Vol. 114, No. 6, 01.05.2018, p. 830-845.

Research output: Contribution to journalArticle

Assenza, MR, Barbagallo, F, Barrios, F, Cornacchione, M, Campolo, F, Vivarelli, E, Gianfrilli, D, Auletta, L, Soricelli, A, Isidori, AM, Lenzi, A, Pellegrini, M & Naro, F 2018, 'Critical role of phosphodiesterase 2A in mouse congenital heart defects', Cardiovascular Research, vol. 114, no. 6, pp. 830-845. https://doi.org/10.1093/cvr/cvy030
Assenza MR, Barbagallo F, Barrios F, Cornacchione M, Campolo F, Vivarelli E et al. Critical role of phosphodiesterase 2A in mouse congenital heart defects. Cardiovascular Research. 2018 May 1;114(6):830-845. https://doi.org/10.1093/cvr/cvy030
Assenza, Maria Rita ; Barbagallo, Federica ; Barrios, Florencia ; Cornacchione, Marisa ; Campolo, Federica ; Vivarelli, Elisabetta ; Gianfrilli, Daniele ; Auletta, Luigi ; Soricelli, Andrea ; Isidori, Andrea M. ; Lenzi, Andrea ; Pellegrini, Manuela ; Naro, Fabio. / Critical role of phosphodiesterase 2A in mouse congenital heart defects. In: Cardiovascular Research. 2018 ; Vol. 114, No. 6. pp. 830-845.
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AU - Vivarelli, Elisabetta

AU - Gianfrilli, Daniele

AU - Auletta, Luigi

AU - Soricelli, Andrea

AU - Isidori, Andrea M.

AU - Lenzi, Andrea

AU - Pellegrini, Manuela

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