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

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.

Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension

“…Furthermore, chronic amphetamine exposure in hypoxic mice leads to suppression of HIF1a (hypoxia-inducible factor 1-a) and disruption of adaptive responses to mitochondrial oxidative stress, resulting in DNA damage and ultimately vascular injury (31). Finally, as with all drugand toxin-related PAH, a minority of exposed individuals develop PAH, suggesting varying susceptibility from a potential "second hit," such as genetic (32), epigenetic, and environmental factors, or even route, chronicity, or dose of administration (33).…”

Regional Variation in Methamphetamine-associated Pulmonary Arterial Hypertension: Who’d Better Call Saul?

“…Previous studies have shown that methamphetamine uptake is highest within the lungs, possibly contributing to direct pulmonary toxicity and vascular damage ( 11 ). Other studies have attributed damage to similarities between methamphetamines and serotonin, as serotonin may promote pulmonary smooth muscle cell proliferation and vascular remodeling or even induce DNA damage and impair the oxidative stress response ( 12 , 13 ). Clinically, there have been few studies specifically evaluating patients with Meth-APAH.…”

Development of amide-based fluorescent probes for selective measurement of carboxylesterase 1 activity in tissue extracts

“…The membranes were then blocked with 3% BSA, incubated with rabbit polyclonal anti-human CES1 antibody (1:5000) and subsequently incubated with secondary goat anti-rabbit IgG (1:5000) (Abcam, Cambridge, MA). Anti-human CES1 antibody was prepared in a manner previously described [12, 27]. Membranes were imaged on a ChemiDoc MP (Bio-Rad, Hercules, CA) using SuperSignal West Femto ECL Detection Reagent (Thermo Scientific, Waltham, MA).…”

“…Additionally, hCE1 is associated with cholesterol ester metabolism, an activity that prevents the conversion of macrophages into foam cells, which are major players in the development of atherosclerosis [11]. hCE1 has also been implicated in the progression of pulmonary arterial hypertension in methamphetamine users [12]. Finally, hCE1 is suspected to mediate tumoricidal activity in monocytes because patients with non-Hodgekins lymphoma and gastrointestinal carcinoma have altered esterase activity in these cells [13].…”