title: Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung.
abstract: There is increasing interest in the potential for metabolic profiling to evaluate the progression of pulmonary hypertension (PH). However, a detailed analysis of the metabolic changes in lungs at the early stage of PH, characterized by increased pulmonary artery pressure but prior to the development of right ventricle hypertrophy and failure, is lacking in a preclinical animal model of PH. Thus, we undertook a study using rats 14 days after exposure to monocrotaline (MCT), to determine whether we could identify early stage metabolic changes prior to the manifestation of developed PH. We observed changes in multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis. Further, our global metabolic profile data compare favorably with prior work carried out in humans with PH. We conclude that despite the MCT-model not recapitulating all the structural changes associated with humans with advanced PH, including endothelial cell proliferation and the formation of plexiform lesions, it is very similar at a metabolic level. Thus, we suggest that despite its limitations it can still serve as a useful preclinical model for the study of PH.
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona, Tucson, Arizona, United States of America.|Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Rafikova
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Meadows
authors.affiliation: Metabolon, Durham, North Carolina, United States of America.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.affiliation: Metabolon, Durham, North Carolina, United States of America.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Division of Neonatology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Emin
authors.initials: E
authors.lastname: Maltepe
authors.affiliation: Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona, Tucson, Arizona, United States of America.|Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.|Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona, Tucson, Arizona, United States of America.|Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Division of Translational and Regenerative Medicine, The University of Arizona, Tucson, Arizona, United States of America.|Department of Medicine, The University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002331:Carnitine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055442:Metabolome / Q000187:drug effects*; D016686:Monocrotaline / Q000008:administration & dosage / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D016686:Monocrotaline; D005978:Glutathione; D002331:Carnitine