Changes in Ca2 influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca has been widely acknowledged, little is known about the role of Na. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na as well as Ca2 levels. In stable coronary artery disease patients ( = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment ( = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na shuttling is required for a full cellular response to inflammation and that inhibition of Na influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na-Ca exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303949PMC
http://dx.doi.org/10.1073/pnas.2207020119DOI Listing

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