P755Molecular mechanisms underlying the beneficial effects of neuregulin-1 in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) leads to right ventricular (RV) failure and death. Neuregulin (NRG)-1 has been implicated in several processes regulating cardiac development, as well as cardiac and vascular homeostasis. It was previously shown, in an experimental model of MCT-induced PAH, that NRG-1 treatment is able to restore PAH-induced severe abnormalities in cardiac function and structure. This study investigated the underlying molecular mechanisms to the beneficial effects of NRG-1 in myocardial function, in the same animal model of induced PAH. Male Wistar rats randomly received monocrotaline (MCT, 60mg/Kg,sc) or vehicle. After 14 days, animals received NRG-1 (40μg/Kg/day,ip) or vehicle, resulting in 4 groups: CTRL; CTRL+NRG-1; MCT; MCT+NRG-1. RV sample collection for were performed 21-24 days after MCT administration. Only significant results (mean±SEM, p<0.05) are given. NRG-1/ErbB system components expressions in MCT animals are changed. We observed increased levels of NRG-1 in RV (11.1±2.8 vs 1.0±0.3 AU, MCT vs CTRL), which were reversed by NRG-1 treatment (MCT+NRG-1: 0.7±0.5 AU), and decreased levels of ErbB4 in all MCT animals (MCT: 0.6±0.2 and MCT+NRG-1: 0.7±0.15 AU). We also found increased levels of ErbB2 (2.0±0.3 AU), ADAM-17 (2.1±0.3 AU) and ADAM-19 (2.7±0.3 AU), and increased eNOS expression (2.0±0.3 AU) in the RV of MCT animals that not reversed with NRG-1 treatment. MCT treatment led to altered GLUT1 expression (4.1±0.5 AU) and NRG-1 treatment attenuated this increase (1.7±0.3 AU). GLUT4 was increased in all animals treated with NRG-1 (CTRL+NRG-1: 1.4±0.1; MCT+NRG-1: 1.5±0.2 AU). Increased RV caspase 3 (MCT: 4.4±0.4 AU) and plasmatic expression of IL-6 and TNF-α (IL6: 2.7±0.7 AU; TNF-α: 1.7±0.3 AU) were attenuated by NRG-1 treatment (caspase 3: 1.7±0.3 AU; IL6: 2.0±0.4 AU; TNF-α: 1.5±0.4 AU). Moreover, we found that the increased expression of BNP (17.5±2.2 AU), ET-1 (5.0±1.2 AU) and HIF-1α (4.3±1.1 AU) observed in MCT animals was attenuated or reversed with NRG-1 therapy (MCT+NRG-1: 5.6±1.9; 1.7±0.7; 1.4±0.1 AU, respectively). In conclusion, we show that NRG-1 treatment is able to restore the changes in expression of markers of cardiac overload, hypertrophy and hypoxia induced by PAH. These beneficial effects of NRG-1 are associated with the modulation of different signaling pathways, namely apoptotic, metabolic, survival/ proliferation, and inflammation pathways.