Lung 18F-Fluorodeoxyglucose Positron Emission Tomography for Diagnosis and Monitoring of Pulmonary Arterial Hypertension
- 15 March 2012
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 185 (6), 670-679
- https://doi.org/10.1164/rccm.201108-1562oc
Abstract
Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer (18)F-fluorodeoxyglucose (FDG). The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1α (HIF-1α), which underlies their glycolytic phenotype. HIF-1α-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.Keywords
This publication has 36 references indexed in Scilit:
- p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in miceAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2011
- Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertensionAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
- Epigenetic Attenuation of Mitochondrial Superoxide Dismutase 2 in Pulmonary Arterial HypertensionCirculation, 2010
- Basic Science of Pulmonary Arterial Hypertension for CliniciansCirculation, 2010
- Hypoxia Inducible-Factor1α Regulates the Metabolic Shift of Pulmonary Hypertensive Endothelial CellsThe American Journal of Pathology, 2010
- The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricleJournal of Molecular Medicine, 2009
- Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by MonocrotalineThe American Journal of Pathology, 2009
- Induction of Pyruvate Dehydrogenase Kinase-3 by Hypoxia-inducible Factor-1 Promotes Metabolic Switch and Drug ResistancePublished by Elsevier BV ,2008
- An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertensionJCI Insight, 2008
- Alterations of cellular bioenergetics in pulmonary artery endothelial cellsProceedings of the National Academy of Sciences of the United States of America, 2007