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      Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension


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          Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH), but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. Although no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH. Furthermore, whole exome sequencing data from 18 METH-PAH patients revealed that 94.4% of METH-PAH patients were heterozygous carriers of a single nucleotide variant (SNV; rs115629050) predicted to reduce CES1 activity. PMVECs transfected with this CES1 variant demonstrated significantly higher rates of METH-induced apoptosis. METH exposure results in increased formation of reactive oxygen species (ROS) and a compensatory autophagy response. Compared with healthy cells, CES1-deficient PMVECs lack a robust autophagy response despite higher ROS, which correlates with increased apoptosis. We propose that reduced CES1 expression/activity could promote development of METH-PAH by increasing PMVEC apoptosis and small vessel loss.

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          Author and article information

          Am J Physiol Lung Cell Mol Physiol
          Am. J. Physiol. Lung Cell Mol. Physiol
          American Journal of Physiology - Lung Cellular and Molecular Physiology
          American Physiological Society (Bethesda, MD )
          1 August 2017
          4 May 2017
          1 August 2018
          : 313
          : 2
          : L252-L266
          [1] 1Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center , Stanford, California;
          [2] 2The Vera Moulton Wall Center for Pulmonary Vascular Medicine, Stanford University Medical Center , Stanford, California;
          [3] 3Stanford Cardiovascular Institute, Stanford University Medical Center , Stanford, California;
          [4] 4University of Illinois College of Medicine, Chicago, Illinois;
          [5] 5Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California Davis , Davis, California;
          [6] 6The Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University , Stanford, California;
          [7] 7Children’s Hospital Helsinki, University of Helsinki , Helsinki, Finland; and
          [8] 8Department of Pathology, Stanford University Medical Center , Stanford, California
          Author notes

          R. T. Zamanian and V. de Jesus Perez contributed equally to this work.

          Address for reprint requests and other correspondence: V. A. de Jesus Perez, Div. of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Dr., Grant S140b. Stanford, CA 94305 (e-mail: vdejesus@ 123456stanford.edu ).
          PMC5582936 PMC5582936 5582936 L-00453-2016 L-00453-2016
          Copyright © 2017 the American Physiological Society
          Funded by: NIH NHLBI K08
          Award ID: HL105884-01
          Funded by: http://doi.org/10.13039/100002291 Pulmonary Hypertension Association (PHA)
          Funded by: http://doi.org/10.13039/100002590 American Lung Association
          Funded by: http://doi.org/10.13039/100000867 Robert Wood Johnson Foundation (RWJF)
          Funded by: http://doi.org/10.13039/100000968 American Heart Association (AHA)
          Funded by: http://doi.org/10.13039/100000066 HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)
          Award ID: R01 ES002710
          Funded by: http://doi.org/10.13039/100000057 HHS | NIH | National Institute of General Medical Sciences (NIGMS)
          Award ID: T32GM099608
          Funded by: NIH
          Award ID: R01 HL134776
          Research Article
          Biomarkers in Lung Diseases: From Pathogenesis to Prediction to New Therapies
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