LAUSR

Significance Inflammation is a key process accompanying cardiovascular disease. Reducing inflammation is therefore an important therapeutic option. We provide evidence, that Na+ and Ca2+ modulation regulate the inflammatory response. Reducing intracellular Na+ pharmacologically using the drug ranolazine reduced the influx of Ca2+ during inflammation and thereby reduced the cellular production of inflammatory mediators. Similarly, reduction of extracellular Na+ and knockdown of a Na+–Ca2+ exchanger led to reduced inflammation. Our in vitro finding translated to in vivo experiments as ranolazine treatment led to reduced atherosclerotic plaque growth, increased plaque stability, and diminished inflammation in a mouse model. Finally, we were able to observe the antiinflammatory effect of Na+ modulation in human patients, demonstrating that inflammation was reduced after treatment with ranolazine.