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

Mark E. Orcholski, Artyom Khurshudyan, Elya A. Shamskhou, Ke Yuan, Ian Y. Chen, Sean D. Kodani, Christophe Morisseau, Bruce D. Hammock, Ellen M. Hong, Ludmila Alexandrova, Tero Pekka Alastalo, Gerald Berry, Roham T. Zamanian, Vinicio A. De Jesus Perez

Research output: Contribution to journalArticle

11 Scopus citations

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 languageEnglish (US)
Pages (from-to)L252-L266
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume313
Issue number2
DOIs
StatePublished - 2017

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ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

Cite this

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., & De Jesus Perez, V. A. (2017). Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension. American Journal of Physiology - Lung Cellular and Molecular Physiology, 313(2), L252-L266. https://doi.org/10.1152/ajplung.00453.2016