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

• Published in: Cardiovascular research 2018-07, Vol.114 (8), p.1165-1177
• Main Authors: Adão, Rui, Mendes-Ferreira, Pedro, Santos-Ribeiro, Diana, Maia-Rocha, Carolina, Pimentel, Luís D, Monteiro-Pinto, Cláudia, Mulvaney, Eamon P, Reid, Helen M, Kinsella, B Therese, Potus, François, Breuils-Bonnet, Sandra, Rademaker, Miriam T, Provencher, Steeve, Bonnet, Sébastien, Leite-Moreira, Adelino F, Brás-Silva, Carmen
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Arterial Pressure - drug effects; Case-Control Studies; Corticotropin-Releasing Hormone - metabolism; Corticotropin-Releasing Hormone - pharmacology; Disease Models, Animal; Exercise Tolerance - drug effects; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Heart Ventricles - physiopathology; Humans; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - physiopathology; Hypertension, Pulmonary - prevention & control; Hypertrophy, Right Ventricular - metabolism; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - prevention & control; Male; Pulmonary Artery - drug effects; Pulmonary Artery - physiopathology; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone - metabolism; Signal Transduction - drug effects; Urocortins - metabolism; Urocortins - pharmacology; Vascular Remodeling - drug effects; Vasodilation - drug effects; Ventricular Dysfunction, Right - metabolism; Ventricular Dysfunction, Right - physiopathology; Ventricular Dysfunction, Right - prevention & control; Ventricular Function, Right - drug effects; Ventricular Remodeling - drug effects
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvy076

Abstract Aims Pulmonary arterial hypertension (PAH) is a devastating disease and treatment options are limited. Urocortin-2 (Ucn-2) has shown promising therapeutic effects in experimental and clinical left ventricular heart failure (HF). Our aim was to analyse the expression of Ucn-2 in human and experimental PAH, and to investigate the effects of human Ucn-2 (hUcn-2) administration in rats with monocrotaline (MCT)-induced pulmonary hypertension (PH). Methods and results Tissue samples were collected from patients with and without PAH and from rats with MCT-induced PH. hUcn-2 (5 μg/kg, bi-daily, i.p., for 10 days) or vehicle was administered to male wistar rats subjected to MCT injection or to pulmonary artery banding (PAB) to induce right ventricular (RV) overload without PAH. Expression of Ucn-2 and its receptor was increased in the RV of patients and rats with PAH. hUcn-2 treatment reduced PAH in MCT rats, resulting in decreased morbidity, improved exercise capacity and attenuated pulmonary arterial and RV remodelling and dysfunction. Additionally, RV gene expression of hypertrophy and failure signalling pathways were attenuated. hUcn-2 treatment also attenuated PAB-induced RV hypertrophy. Conclusions Ucn-2 levels are altered in human and experimental PAH. hUcn-2 treatment attenuates PAH and RV dysfunction in MCT-induced PH, has direct anti-remodelling effects on the pressure-overloaded RV, and improves pulmonary vascular function.