YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice

Background: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and elevation of pulmonary arterial pressure, leading to right ventricular failure and eventual death. Currently, no curative therapy for PAH is available, and the overall prognosis is very poor. Recently, direct activators of soluble guanylyl cyclase (sGC) have been tested as a novel therapeutic modality in experimental models of pulmonary arterial hypertension (PAH). Objective: In this study, we used in vitro and in vivo models to evaluate the therapeutic potential of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a dual functioning chemical, as a direct activator of guanylyl cyclase and an inhibitor of hypoxia-inducible factor-1. Methods: We analyzed the effects of YC-1 on cell proliferation and the levels of p21 and p53 in human pulmonary artery smooth muscle cells (HPASMCs) under hypoxia. We also determined the effects of YC-1 on expression of endothelin-1 (ET-1) and phosphorylation status of endothelial nitric oxide synthase (eNOS) at Ser(1179) in human pulmonary artery endothelial cells (HPAECs) under hypoxia. In mice, hypoxic PAH was induced by exposure to normobaric hypoxic conditions for 28 days. To assess preventive or therapeutic effects, randomized mice were subjected to once daily i.p. injections of YC-1 for the entire hypoxic period (5 mg/kg) or for the last seven days of a 28-day hypoxic period (5 and 10 mg/kg). On day 28, we measured the right ventricular systolic pressure (RVSP) and determined the degrees of right ventricular hypertrophy (RVH) and vascular remodeling. Results: In HPASMCs, YC-1 inhibited hypoxia-induced proliferation and induction of p53 and p21 in a concentration-dependent manner. Also, YC-1 suppressed the hypoxia-induced expression of ET-1 mRNA and dephosphorylation of eNOS at Ser(1179) in HPAECs. In the preventive in vivo model, a daily dose of 5 mg/kg YC-1 significantly prevented the elevation of RVSP, development of RVH, and pulmonary vascular remodeling, which were caused by hypoxic exposure. In the therapeutic model, YC-1 at daily doses of 5 and 10 mg/kg alleviated RVH and pulmonary vascular remodeling but did not prevent the elevation of RVSP. Conclusions: Our results indicate that YC-1 prevents the development of hypoxia-induced PAH in a preventive model and alleviates RVH and pulmonary vascular remodeling in a therapeutic model. Therefore, these data imply that YC-1 has therapeutic potential for use in a single or combination therapy for PAH. (C) 2011 Elsevier Ltd. All rights reserved.