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

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.

Adão R ，Mendes-Ferreira P ，Maia-Rocha C ，Santos-Ribeiro D ，Rodrigues PG ，Vidal-Meireles A ，Monteiro-Pinto C ，Pimentel LD ，Falcão-Pires I ，De Keulenaer GW ，Leite-Moreira AF ，Brás-Silva C ... -  《-》

Neuregulin-1 improves right ventricular function and attenuates experimental pulmonary arterial hypertension.

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). 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. 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.

Mendes-Ferreira P ，Maia-Rocha C ，Adão R ，Mendes MJ ，Santos-Ribeiro D ，Alves BS ，Cerqueira RJ ，Castro-Chaves P ，Lourenço AP ，De Keulenaer GW ，Leite-Moreira AF ，Brás-Silva C ... -  《-》

Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca(2+) was increased and Ca(2+) release was facilitated. K(+) currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca(2+) content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

Rocchetti M ，Sala L ，Rizzetto R ，Staszewsky LI ，Alemanni M ，Zambelli V ，Russo I ，Barile L ，Cornaghi L ，Altomare C ，Ronchi C ，Mostacciuolo G ，Lucchetti J ，Gobbi M ，Latini R ，Zaza A ... -  《-》

Pulmonary artery banding is a relevant model to study the right ventricular remodeling and dysfunction that occurs in pulmonary arterial hypertension.

Akazawa Y ，Okumura K ，Ishii R ，Slorach C ，Hui W ，Ide H ，Honjo O ，Sun M ，Kabir G ，Connelly K ，Friedberg MK ... -  《-》

Urocortin-2 improves right ventricular function and attenuates pulmonary arterial hypertension.

Adão R ，Mendes-Ferreira P ，Santos-Ribeiro D ，Maia-Rocha C ，Pimentel LD ，Monteiro-Pinto C ，Mulvaney EP ，Reid HM ，Kinsella BT ，Potus F ，Breuils-Bonnet S ，Rademaker MT ，Provencher S ，Bonnet S ，Leite-Moreira AF ，Brás-Silva C ... -  《-》