Neuregulin-1 improves right ventricular function and attenuates experimental pulmonary arterial hypertension.
OBJECTIVE
Pulmonary arterial hypertension (PAH) is a serious disease that affects both the pulmonary vasculature and the right ventricle (RV). Current treatment options are insufficient. The cardiac neuregulin (NRG)-1/ErbB system is deregulated during heart failure, and treatment with recombinant human NRG-1 (rhNRG-1) has been shown to be beneficial in animal models and in patients with left ventricular (LV) dysfunction. This study aimed to evaluate the effects of rhNRG-1 in RV function and pulmonary vasculature in monocrotaline (MCT)-induced PAH and RV hypertrophy (RVH).


RESULTS
Male wistar rats (7- to 8-weeks old, n = 78) were injected with MCT (60 mg/kg, s.c.) or saline and treated with rhNRG-1 (40 µg/kg/day) or vehicle for 1 week, starting 2 weeks after MCT administration. Another set of animals was submitted to pulmonary artery banding (PAB) or sham surgery, and followed the same protocol. MCT administration resulted in the development of PAH, pulmonary arterial and RV remodelling, and dysfunction, and increased RV markers of cardiac damage. Treatment with rhNRG-1 attenuated RVH, improved RV function, and decreased RV expression of disease markers. Moreover, rhNRG-1 decreased pulmonary vascular remodelling and attenuated MCT-induced endothelial dysfunction. The anti-remodelling effects of rhNRG-1 were confirmed in the PAB model, where rhNRG-1 treatment was able to attenuate PAB-induced RVH.


CONCLUSIONS
rhNRG-1 treatment attenuates pulmonary arterial and RV remodelling, and dysfunction in a rat model of MCT-induced PAH and has direct anti-remodelling effects on the pressure-overloaded RV.
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Pedro
P
Mendes-Ferreira
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Carolina
C
Maia-Rocha
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Rui
R
Adão
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Maria José
MJ
Mendes
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Diana
D
Santos-Ribeiro
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Bárbara Silvana
BS
Alves
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Rui João
RJ
Cerqueira
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Paulo
P
Castro-Chaves
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
André Pedro
AP
Lourenço
Laboratory of Physiology, University of Antwerp, Antwerpen, Belgium.
Gilles W
GW
De Keulenaer
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
Adelino Ferreira
AF
Leite-Moreira
Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Cardiovascular Research and Development Centre, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal Faculty of Nutrition and Food Sciences, University of Porto, Porto, Portugal carmensb@med.up.pt.
Carmen
C
Brás-Silva
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D008297:Male; D020890:Neuregulin-1 / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects*
D020890:Neuregulin-1; D011994:Recombinant Proteins
Cardiac hypertrophy; Endothelial dysfunction; Neuregulin; Pulmonary hypertension; Right ventricular function