Research
Methamphetamine and PAH
During the 1950s through the 1980s three amphetamine-like drugs were commonly prescribed as diet pills, and they worked well. However, despite their effective treatment of obesity, as well as drug dependence and other psychiatric disorders, these anorexigens were taken off the market due to their strong association with the development of PAH. The illicit recreational drug methamphetamine (Meth) has similarly been found to be a likely causal factor in the development of PAH. Our lab has taken particular interest in this phenomenon because the Stanford pulmonary clinic sees a large number of PAH patients that report exposure to Meth. Starting with these patients’ blood samples, we ran a Whole Exome Sequencing genetic screen in search of gene variants that correlate with Meth exposure. At the top of the list was Carboxylesterase 1 (CES1), a gene highly expressed in the liver and is thought to be an important mediator of drug metabolism. We found it to be mutated at critical sites in all included Meth-PAH samples as well as in 30% of non-Meth-PAH samples. Running with this result, we moved to in vitro assays to ask what the role of CES1 is in Pulmonary Microvascular Endothelial Cells (PMVECs) and whether the absence of CES1 in PMVECs effects their survival when exposed to Meth. As expected, we found that Meth is toxic to PMVECs and induces cell death, but interestingly we found that cells lacking CES1 were more vulnerable to the toxicity as they displayed even greater levels of cell death. The mechanism is still unclear to us, but we believe that CES1-deficient PMVECs have dysfunctional autophagy that allows for excessive Meth-induced accumulation of reactive oxygen species leading to increased cell death. The underpinnings of this mechanism may provide insight into the etiology of Meth-induced PAH, from which we may learn about the development of any form of PAH since Meth-PAH patients present with the same pathology as patients with hereditary, associated and idiopathic PAH.