Ana Gabriela de Oliveira do Rêgo

Dottoressa

ciclo: XXXIV


tutor: Fabio Naro
supervisore: Manuela Pellegrini

Titolo della tesi: Role of phosphodiesterase type 5 in the induction of cardiac hypertrophy

Rationale: Cardiac performance is closely associated with the stimulation of the β-adrenergic system with consequent modulation of cyclic nucleotides, important mediators of the intracellular cardiac response. In particular, during the chronic overload of the left ventricle, the β-adrenergic signaling leads to cardiac hypertrophy and pathological remodeling that, ultimately, may result in heart failure. Phosphodiesterase type 5 (PDE5A), an enzyme that hydrolyzes cGMP nucleotide, seems to regulate several aspects of heart physiology, indeed its inhibition improves left ventricular heart function under pathological conditions. However, the exact mechanisms underlined the beneficial effect of PDE5A inhibition, the extent of counteracting cardiac hypertrophy and the potential structural role versus the enzymatic activity need to be clarified, in order to safely utilize PDE5A targeting for a therapeutic approach. Aim: Investigation of PDE5A role in the development and progression of cardiac hypertrophy, by using genetically modified mice deficient in PDE5A protein (PDE5A-/-). Methods and Results: Heart Rate (HR) analysis was initially performed, with Langendorff system, in hearts from PDE5+/+ and PDE5A-/- mice. The HR at baseline and after stimulation with the isoproterenol, a β-adrenergic agonist, was similar in both genotypes, suggesting that PDE5A is not crucial for heart chronotropy under physiological conditions. As a model of cardiac hypertrophy, Transverse Aortic Constriction (TAC) was performed. Both mild and severe cardiac hypertrophy was induced in PDE5A+/+ and PDE5A-/- mice. Results showed that cardiac hypertrophy was surprisingly induced also in PDE5A-/- mice, 4 weeks after TAC surgery, with similar alterations of cardiac function, morphology, fibrosis and expression of molecular markers compared to PDE5A+/+ mice. The use of the PDE5A inhibitor, sildenafil-citrate, was able to partially restore mild cardiac hypertrophy at the morpho-functional and molecular levels in PDE5A+/+ mice, whereas, no improvement was observed in PDE5A-/- mice. Furthermore, in the severe cardiac hypertrophy model, the beneficial effects of sildenafil were not observed even in PDE5A+/+ mice. To understand why PDE5A deficient mice developed cardiac hypertrophy whereas sildenafil treated mice did not, a structural role of PDE5A was hypothesized. Thus co-immunoprecipitation analysis were performed and results seem to indicate that the drug modulate the interaction of PDE5A with the sarcomeric protein, troponin I (TnI). Conclusions: The study clarified some aspects regarding the role of PDE5A signaling in cardiac hypertrophy. PDE5A inhibition is able to counteract the condition of mild hypertrophy at 4 weeks after surgery, however lack of PDE5A does not protect from cardiac hypertrophy induction as well as sildenafil in severe hypertrophy. The difference between the pharmacological and genetic approach targeting PDE5A could be due to the ability of sildenafil to modulate PDE5A protein interactions under mild hypertrophy.

Produzione scientifica

  • 11573/1644142 - 2016 - Filarioids infecting dogs in northeastern Brazil (01a Articolo in rivista)
    DE OLIVEIRA DO REGO, ANA GABRIELA; OTRANTO, DOMENICO
  • 11573/1644162 - 2017 - Cercopithifilaria bainae in Rhipicephalus sanguineus sensu lato ticks from dogs in Brazil (01a Articolo in rivista)
    DE OLIVEIRA DO REGO, ANA GABRIELA
  • 11573/1644169 - 2018 - Screening of Cercopithifilaria bainae and Hepatozoon canis in ticks collected from dogs of Northeastern Brazil (01a Articolo in rivista)
    OTRANTO, DOMENICO; DE OLIVEIRA DO REGO, ANA GABRIELA; GIANNELLI, ALESSANDRO
  • 11573/1663501 - 2023 - Phosphodiesterase 5a signalling in skeletal muscle pathophysiology (01a Articolo in rivista)
    DE ARCANGELIS, VALERIA; DE ANGELIS, LUCIANA; BARBAGALLO, FEDERICA; CAMPOLO, FEDERICA; DE OLIVEIRA DO REGO, ANA GABRIELA; NARO, FABIO; GIORGI, MAURO; MONACO, LUCIA

© Università degli Studi di Roma "La Sapienza" - Piazzale Aldo Moro 5, 00185 Roma