期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：29
DOI：10.1073/pnas.2207020119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Inflammation is a key process accompanying cardiovascular disease. Reducing inflammation is therefore an important therapeutic option. We provide evidence, that Na
+ and Ca
2+ modulation regulate the inflammatory response. Reducing intracellular Na
+ pharmacologically using the drug ranolazine reduced the influx of Ca
2+ during inflammation and thereby reduced the cellular production of inflammatory mediators. Similarly, reduction of extracellular Na
+ and knockdown of a Na
+–Ca
2+ 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.
Changes in Ca2
+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca
2+ 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 (
n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (
n = 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
2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.
