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Title
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Neuregulin-1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Clinical and experimental pharmacology and physiology
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Publication
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2019
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ISSN
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14401681
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DOI
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10.1111/1440-1681.13043
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Volume/pages
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46
:3
(2019)
, p. 255-265
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ISI
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000459826000007
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Pubmed ID
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30339273
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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