Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension.

Endothelial dysfunction plays a principal role in the pathogenesis of pulmonary arterial hypertension (PAH), which is a fatal disease with limited effective clinical treatments. Mitochondrial dysregulation and oxidative stress are involved in endothelial dysfunction. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1α in hypoxia-induced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1α expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1α in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1α inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1α decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NF-κB activation and increased ATP formation and endothelial nitric oxide synthase (eNOS) phosphorylation. Furthermore, hypoxia-induced changes in the mean pulmonary arterial pressure and right heart hypertrophy were nearly normal after intervention. These results suggest that PGC-1α is associated with endothelial function in hypoxia-induced PAH and that improved endothelial function is associated with improved cellular mitochondrial respiration, reduced inflammation and oxygen stress, and increased PGC-1α expression. Taken together, these findings indicate that PGC-1α may be a new therapeutic target in PAH.