Proton pump inhibitors (PPIs) were found to directly interact with the active site of dimethylarginine dimethylaminohydrolase 1 (DDAH1), a critical cardiovascular enzyme. It is through this interaction that PPIs are hypothesized to increase cardiovascular risk, according to study data published in Biochimica et Biophysica Acta – General Subjects.
PPIs are commonly used in the treatment of gastroesophageal reflux disease, though their prolonged use is associated with major adverse cardiovascular events. Ex vivo studies and animal models have found that PPIs inhibit the enzymatic activity of DDAH1, thereby increasing plasma levels of DDAH1’s substrate, asymmetric dimethylarginine (ADMA). The resultant elevated concentrations of ADMA, a nitric oxide synthase inhibitor, are hypothesized to increase the risk for cardiovascular events in PPI users.
To confirm this mechanism of PPI-induced cardiovascular risk in humans, investigators performed enzymatic assays, molecular modeling, X-ray crystallography, and mass spectrometry on DDAH1 enzymes treated with esomeprazole, a prototype PPI. Molecular docking studies were performed to model the interaction of DDAH1 with esomeprazole.
In a cell-based assay where vascular endothelial cells were treated with esomeprazole or control, ADMA concentration was significantly elevated following esomeprazole exposure, suggesting significantly inhibited DDAH1 activity. Crystallography confirmed that esomeprazole interacts with the active site of DDAH1, specifically through covalent docking with the cysteine (Cys273) side chain. The relationship was dose-dependent, with greater doses of esomeprazole conferring greater concentrations of ADMA. In mass spectrometry studies, esomeprazole was again found to directly target cysteine to inactivate DDAH1.
Results from these molecular studies provide context for the apparent association between PPI use and cardiovascular events. By elucidating the mechanism through which PPIs inhibit DDAH1 activity, investigators provide a basis for further preclinical and clinical studies.
“Our study calls for pharmacovigilance studies to monitor adverse cardiovascular events in chronic PPI users,” the study authors wrote.
Smith CA, Ebrahimpour A, Novikova L, et al. Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: insights into the cardiovascular risk of proton pump inhibitors. Biochim Biophys Acta Gen Subj. Published online April 25, 2022. doi:10.1016/j.bbagen.2022.130149