Adao, Rui

Bras-Silva, Carmen

De Keulenaer, Gilles

Falcao-Pires, Ines

Leite-Moreira, Adelino F.

Maia-Rocha, Carolina

Mendes-Ferreira, Pedro

Monteiro-Pinto, Claudia

Pimentel, Luis D.

Rodrigues, Patricia Goncalves

Santos-Ribeiro, Diana

Vidal-Meireles, Andre

Abstract: We have previously shown that treatment with recombinant human neuregulin-1 (rhNRG-1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)-induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG-1 treatment showed direct myocardial anti-remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG-1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG-1 treatment on ventricular passive stiffness in RV and LV samples from MCT-induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling-associated genes and calcium handling proteins. Chronic rhNRG-1 treatment decreased passive tension development in RV and LV isolated from animals with MCT-induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG-1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB-induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac-specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG-1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling

Institutional Repository Universiteit Antwerpen

Neuregulin-1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension

Neuregulin-1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension

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Institutional Repository Universiteit Antwerpen