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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | L252-L266 |
| Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Volume | 313 |
| Issue number | 2 |
| DOIs | |
| State | Published - 2017 |
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ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Cell Biology
- Physiology (medical)
Cite this
Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension. / 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.; De Jesus Perez, Vinicio A.
In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 313, No. 2, 2017, p. L252-L266.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension
AU - Orcholski, Mark E.
AU - Khurshudyan, Artyom
AU - Shamskhou, Elya A.
AU - Yuan, Ke
AU - Chen, Ian Y.
AU - Kodani, Sean D.
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Hong, Ellen M.
AU - Alexandrova, Ludmila
AU - Alastalo, Tero Pekka
AU - Berry, Gerald
AU - Zamanian, Roham T.
AU - De Jesus Perez, Vinicio A.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85026740060&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026740060&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00453.2016
DO - 10.1152/ajplung.00453.2016
M3 - Article
C2 - 28473326
AN - SCOPUS:85026740060
VL - 313
SP - L252-L266
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 2
ER -