title: A Biochemical Approach to Understand the Pathogenesis of Advanced Pulmonary Arterial Hypertension: Metabolomic Profiles of Arginine, Sphingosine-1-Phosphate, and Heme of Human Lung.
abstract: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Yidan D
authors: YD
authors: Zhao
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Lei
authors: L
authors: Chu
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Kathleen
authors: K
authors: Lin
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Elise
authors: E
authors: Granton
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Li
authors: L
authors: Yin
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Jenny
authors: J
authors: Peng
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Michael
authors: M
authors: Hsin
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Licun
authors: L
authors: Wu
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Amy
authors: A
authors: Yu
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Thomas
authors: T
authors: Waddell
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Shaf
authors: S
authors: Keshavjee
authors: Clinical Studies Resource Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: John
authors: J
authors: Granton
authors: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Marc
authors: M
authors: de Perrot
mesh_terms: D000328:Adult; D001120:Arginine / Q000032:analysis*; D005260:Female; D006418:Heme / Q000032:analysis*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism*; D008246:Lysophospholipids / Q000032:analysis*; D008297:Male; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000032:analysis; D066253:Vascular Remodeling
chemical_list: D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D009569:Nitric Oxide; D006418:Heme; D001120:Arginine; D013110:Sphingosine