B.S. Alves

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

AIMS 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). METHODS AND 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. CONCLUSION 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.

Reverse myocardial effects of intermedin in pressure-overloaded hearts: role of endothelial nitric oxide synthase activity

Intermedin (IMD) is a cardiac endogenous peptide upregulated in several models of heart disease. We show a depressant effect of IMD1−47 on contractility of the normal myocardium, mediated by increased nitric oxide (NO) production due to endothelial nitric oxide synthase (eNOS) phosphorylation. In rat models of cardiac hypertrophy or NO deficiency, IMD1−47 enhances contractility and hastens relaxation associated with phospholamban phosphorylation. This opposing response in normal and diseased myocardium is due to impairment of IMD1−47‐induced eNOS phosphorylation. The results reveal distinct myocardial effects and subcellular mechanisms for IMD1−47 in the hypertrophic heart, suggesting a key role of cardiac endothelial dysfunction with potential pathophysiological relevance.