CALL FOR PAPERS Biomarkers in Lung Diseases: from Pathogenesis to Prediction to New Therapies Suppression of endothelial PGC-1 is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension

Ye JX, Wang SS, Ge M, Wang DJ. Suppression of endothelial PGC-1 is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 310: L1233–L1242, 2016. First published April 15, 2016; doi:10.1152/ajplung.00356.2015.— 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 receptorcoactivator-1 (PGC-1 ) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1 in hypoxiainduced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1 expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1 in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1 inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1 decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NFB 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-1 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-1 expression. Taken together, these findings indicate that PGC-1 may be a new therapeutic target in PAH.