REDUCED CARBOXYLESTERASE 1 IS ASSOCIATED WITH ENDOTHELIAL INJURY IN METHAMPHETAMINE INDUCED PULMONARY ARTERIAL HYPERTENSION. American journal of physiology. Lung cellular and molecular physiology 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., Berry, G., Zamanian, R. T., de Jesus Perez, V. A. 2017: ajplung 00453 2016-?


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. While 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 to 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.

View details for DOI 10.1152/ajplung.00453.2016

View details for PubMedID 28473326