title: Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: Department of Cardio-Thoracic Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; and.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Ye
authors.affiliation: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Department of Cardio-Thoracic Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; and.
authors.forename: Min
authors.initials: M
authors.lastname: Ge
authors.affiliation: Department of Cardio-Thoracic Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; and glyy1234@aliyun.com.
authors.forename: Dong-Jin
authors.initials: DJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000502:physiology*; D011651:Pulmonary Artery / Q000473:pathology; D017207:Rats, Sprague-Dawley
chemical_list: D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D009569:Nitric Oxide
keywords: endothelial dysfunction; hypoxia; mitochondria; proliferator-activated receptor-γ coactivator-1α; pulmonary arterial hypertension