VPO1/HOCl/ERK pathway mediates the right ventricular remodeling in rats with hypoxic pulmonary hypertension

Right ventricular (RV) remodeling is a major feature of pulmonary arterial hypertension (PAH). Vascular peroxidase 1 (VPO1) is reported to participate in the process of PAH. This study aims to explore whether VPO1 contributes to hypoxia-induced cardiac hypertrophy and the underlying mechanisms. SD rats were exposure to continuous hypoxia (10% O₂) for 3 weeks, which showed RV hypertrophy (increases in the ratio of RV weight to tibia length, cardiac cell size and hypertrophic markers), concomitant with upregulation of VPO1, elevation in hypochlorous acid (HOCl) production and ERK phosphorylation. In hypoxia (3% O₂)-induced hypertrophic H9c2 cells, similar characteristics of cardiac hypertrophy to that of hypoxia-treated rats were observed. Administration of VPO1 siRNA or NaHS (the HOCl inhibitor) suppressed HOCl production, ERK phosphorylation, and cardiac hypertrophy. Replacement of hypoxia with NaClO (exogenous HOCl) could also induce cardiac cell hypertrophy and activate ERK signaling pathway. In addition, hypoxia-induced cardiac hypertrophy could be blocked by PD98059 (the ERK-specific inhibitor). Based on these observations, we conclude that VPO1 promotes RV remodeling in PAH rats through catalyzing HOCl production, leading to the activation of ERK signaling. Thus, VPO1 may have the potential as a therapeutic target for PAH.