title: Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and excessive growth and dysfunction of the endothelial cells that line the arteries in PAH lungs. Establishment of methods for culture of pulmonary artery endothelial cells from PAH lungs has provided the groundwork for mechanistic translational studies that confirm and extend findings from model systems and spontaneous pulmonary hypertension in animals. Endothelial cell hyperproliferation, survival, and alterations of biochemical-metabolic pathways are the unifying endothelial pathobiology of the disease. The hyperproliferative and apoptosis-resistant phenotype of PAH endothelial cells is dependent upon the activation of signal transducer and activator of transcription (STAT) 3, a fundamental regulator of cell survival and angiogenesis. Animal models of PAH, patients with PAH, and human PAH endothelial cells produce low nitric oxide (NO). In association with the low level of NO, endothelial cells have reduced mitochondrial numbers and cellular respiration, which is associated with more than a threefold increase in glycolysis for energy production. The shift to glycolysis is related to low levels of NO and likely to the pathologic expression of the prosurvival and proangiogenic signal transducer, hypoxia-inducible factor (HIF)-1, and the reduced mitochondrial antioxidant manganese superoxide dismutase (MnSOD). In this article, we review the phenotypic changes of the endothelium in PAH and the biochemical mechanisms accounting for the proliferative, glycolytic, and strongly proangiogenic phenotype of these dysfunctional cells, which consequently foster the panvascular progressive pulmonary remodeling in PAH.
authors.affiliation: Departments of Pathobiology, Lerner Research Institute, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA. xuw@ccf.org
authors.forename: Weiling
authors.initials: W
authors.lastname: Xu
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000502:physiology; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology
chemical_list: D000975:Antioxidants; D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide