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

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Orcholski , M E , Khurshudyan , A , Shamskhou , E A , Yuan , K , Chen , I Y , Kodani , S D , Morisseau , C , Hammock , B D , Hong , E M , Alexandrova , L , Alastalo , T-P , Berry , G , Zamanian , R T & Perez , V A D J 2017 , ' Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension ' , American Journal of Physiology. Lung Cellular and Molecular Physiology , vol. 313 , no. 2 , pp. L252-L266 . https://doi.org/10.1152/ajplung.00453.2016

Title: Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension
Author: Orcholski, Mark E.; Khurshudyan, Artyom; Shamskhou, Elya A.; Yuan, Ke; Chen, Ian Y.; Kodani, Sean D.; Morisseau, Christophe; Hammock, Bruce D.; Hong, Ellen M.; Alexandrova, Ludmila; Alastalo, Tero-Pekka; Berry, Gerald; Zamanian, Roham T.; Perez, Vinicio A. de Jesus
Contributor: University of Helsinki, Clinicum
Date: 2017-08
Language: eng
Number of pages: 15
Belongs to series: American Journal of Physiology. Lung Cellular and Molecular Physiology
ISSN: 1040-0605
URI: http://hdl.handle.net/10138/297910
Abstract: 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.
Subject: ENDOPLASMIC-RETICULUM
OXIDATIVE STRESS
DRUG-METABOLISM
AUTOPHAGIC FLUX
GENE-EXPRESSION
UNITED-STATES
CELL-DEATH
IN-VIVO
ABUSE
MUTATIONS
3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
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