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Pulmonary arterial hypertension (PAH), characterized by excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs), is closely associated with the imbalance in vasoactive mediators and massive remodeling of pulmonary vasculature. DJ-1/park7, a multifunctional protein, plays a critical defense role in several cytobiological activity, such as transcriptional regulation, anti-oxidative stress and tumor formation. In this study, we investigated the effects of DJ-1 on hypoxia-induced PAH model rats and PASMCs, as well as its possible molecular mechanism. First, the low expressions of DJ-1 and caveolin-1 (Cav-1) were synchronously detected in lung tissue of PAH model rats and hypoxia-induced PASMCs by Western blot. Then, the DJ-1 wild type (WT) or Knock out (KO) rats were exposed to chronic hypoxia to mimic a hypoxic PAH condition. The protein level of Cav-1 was markedly decreased in the tissue of DJ-1 KO rats, and additionally lower in tissue of the hypoxia group than that in the normoxia group for DJ-1 WT and KO rats. In vivo, hemodynamic data showed that the pulmonary arterial pressure (mPAP), right ventricle systolic pressure (RVSP) and pulmonary arterial systolic pressure (PASP), as well as the weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio of PAH model rats were higher in the DJ-1 KO group than those in the DJ-1 WT group. Moreover, knockout of DJ-1 also results in the phenotype switch from contractile to synthetic PASMC, which is reflected by reduced calponin and SM22α expressions. In vitro, DJ-1 overexpression reversed hypoxia-induced elevation of PASMC cell proliferation, migration and Ca2+ concentration, which were not obviously observed in Cav-1 shRNA (sh-Cav-1) and DJ-1 co-transfected cells. Then the increased levels of calponin and SM22α were detected in the DJ-1 group; similarly those levels were not changed in the DJ-1+sh-Cav-1 group. Finally, the expression of TGFβ1, p-Smad2 and p-Smad3 were obviously decreased in the ad-DJ-1 group, however those were all elevated in the DJ-1 and sh-Cav-1 co-transfected groups. In conclusion, these results indicate that DJ-1 may alleviate hypoxia-induced PASMCs injury by Cav-1 through inhibiting the TGFβ/Smad signaling pathway.Knockout of DJ-1-aggravated hypoxic pulmonary arterial hypertension of rats.Overexpression of DJ-1 alleviated PASMs injury induced by hypoxia.DJ-1 alleviated hypoxia-induced PASMCs injury via Cav-1 by inhibiting TGFβ/Smad.