Role Of Osteoprotegerin In Pulmonary Hypertension

Background:Pulmonary arterial remodeling characterized by increased vascular smooth muscle cells prolifertation is a common lesion seen in the life-threatening pulmonary hypertension?PH?.Current therapies fail to fully reverse vascular remodeling and improve long-term survival.Therefore,discovery of new molecular targets or signaling pathways therapeutically capable of inhibiting remodeling of pulmonary arteries is urgently needed.Osteoprotegerin?OPG?is a member of the tumor-necrosis-factor?TNF?receptor superfamily,and is expressed and secreted by a variety of tissues,including heart and lung.However,wether it is involved in the related physical and pathological process and how to play its role is still not clear.A small sample of clinical data suggested a correlation between OPG and PH for that serum concentrations of OPG were higher in idiopathic pulmonary hypertension patients and associated with indicators of disease severity and prognosis.Here,we aimed to investigate whether OPG plays a role in PH progression through experiments in vitro and in vivo.Methods and results:?1?Clinical research:Serum OPG levels in 70 patients with PH and75 controls were enrolled.OPG concentrations were elevated in PH patients as compared to controls.Additionally,serum OPG levels correlated with disease severity in PH patients as represented by World Health Organization functional classifications and 6-min walking distance covered before and after treatment.?2?Animal experiment:Eight to ten-week-old OPG^-/-and WT mice were placed in normoxia?21%O₂?or mobaric hypoxia?10%O₂?for3 weeks,the right ventricular systolic pressure?PASP?and right ventricular hypertrophy was assessd;Lung sections were stained with hematoxylin and eosin for morphometric analysis.In a hypoxia-induced PH mouse model,OPG deletion attenuated PH severity by reducing vascular remodeling.?3?In vitro experiment:The pulmonary artery smooth muscle cells?PASMCs?were isolated from the pulmonary vessles and cultured in vitro.For experiment,cells were maintained in hypoxia?5%CO₂,1%O₂?conditions or normoxia?5%CO₂,21%O₂?conditions for 24-48h with or without stimulation of recombinant OPG.OPG expression was strikingly elevated in lungs and pulmonary arteries of hypoxia-treated mice,and in cultured mouse and human PASMCs,indicating that OPG was able to promote PASMCs proliferation under different conditions.Conclusions:OPG is involved in the development of PH by regulating PASMC proliferation.Our results indicated that OPG may be a potential biomarker and therapeutic target in PH.