Can Endothelial Injury Provide the Passage to Explain the Vascular Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are a widely used category of drug for past 20 years. Originally requiring a prescription, PPIs were used to treat peptic ulcer and gastroesophageal reflux disease. PPIs now are readily available over the counter, and their use is often unmonitored. Over utilization of PPIs for inappropriate indications and their use for durations beyond that indicated in original recommendations have been reported in both hospital and ambulatory settings.1,2 Over the past few years, the safety of long-term PPI use has come into question with observational studies reporting increased prevalence of dementia, myocardial infarction, and renal failure in people who use long-term PPIs.3–6 However, no causative mechanism for the adverse effects of PPI has been established.Article, see p e36 Following their recent report of association of PPI use with myocardial infarction in the general population,5 in this issue of Circulation Research , Yepuri et al7 used a series of invitro studies using human microvascular endothelial cells (EC) treated with clinically relevant concentrations of the PPI, esomeprazole. They showed reduced lysosomal cathepsin-B and phosphatase, and increased lysosomal protein aggregates in ECs treated with esomeprazole versus controls, indicating impaired lysosomal proteostasis. Treatment with esomeprazole increased production of EC superoxide anions, decreased eNOS (endothelial nitric oxide synthase) and iNOS (inducible nitric oxide synthase) expression, and reduced nitric oxide (NO) production. In matrigel assays, treatment with esomeprazole reduced microvascular EC proliferation and network formation. Finally, the authors show that esomeprazole treatment accelerated EC senescence as …