Background: Right ventricular (RV) failure is an important prognostic factor for pulmonary arterial hypertension (PAH). A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8) is a secreted extracellular enzyme and is expressed specifically in the lung and the heart.Methods and Results: To explore a novel therapeutic target of PAH and RV failure, we performed microarray analysis of pulmonary artery smooth muscle cells (PASMCs) from PAH patients and controls, and found a significant up-regulation of ADAMTS8 in PAH-PASMCs compared with controls. Protein levels of ADAMTS8 were also significantly increased in PAH-PASMCs compared with controls. Additionally, hypoxia (10% O2) increased ADAMTS8 protein in the lung in wild-type mice (P<0.05, n=5-10). To elucidate the role of ADAMTS8 in pulmonary hypertension (PH), we used vascular smooth muscle cell-specific ADAMTS8-deficient mice (ADAMTS8). ADAMTS8 mice exposed to hypoxia for 4 weeks showed significantly reduced RV systolic pressure (33.5±0.3 vs. 38.9±0.4 mmHg), RV hypertrophy (0.26±0.06 vs. 0.33±0.09), and vascular remodeling compared with controls (all P<0.05, n=10 each). Moreover, ADAMTS8 mice showed significantly reduced MMP activities and reactive oxygen species (ROS) levels in pulmonary arteries. Human recombinant ADAMTS8 (hrADAMTS8) activated MMPs and promoted proliferation in PAH-PASMCs. Additionally, hrADAMTS8 treatment inhibited VEGFR2/AMPK signaling, reduced PA endothelial cell proliferation, and induced endothelial dysfunction. In contrast, PASMCs from ADAMTS8 mice showed reduced cell proliferation, migration, and ROS levels, which accompanied an improved mitochondrial function especially in hypoxia (1% O2, all P<0.05, n=6-9). Finally, there was no significant difference in RV systolic pressure between cardiac-specific ADAMTS8-deficient mice (ADAMTS8) and controls after chronic hypoxia for 4 weeks (10% O2), whereas ADAMTS8 showed enhanced angiogenesis, reduced ischemia/fibrosis, and resultant improved exercise capacity (treadmill) compared with controls (288±20 vs. 215±18 m, all P<0.05, n=10-20).Conclusions: ADAMTS8 could be a novel therapeutic target for PAH and RV failure.