Background: Active shuttling of Ca²⁺ is required for inflammatory signal progression. During muscle cell activation this Ca²⁺ import is supported by an efflux of Na⁺. Whether this system is also required during inflammation is so far unknown.

Aims: To determine if Na⁺ content of a cell modulates its inflammatory response in vitro and in vivo using an approved compound that reduces cellular Na⁺ intake termed Ranolazine.

Methods: Antiinflammatory properties of ranolazine were tested in a LDL-R^-/- atherosclerotic mouse model and in a patient cohort involving 47 patients randomized to either ranolazine or control treatment for 3 months. The mode of action of ranolazine was determined in an endothelial cell culture model using human umbilical vein endothelial cells.

Results: Atherosclerotic plaque analysis in an atherosclerotic mouse model on a high fat diet demonstrated reduced atherosclerotic plaque burden, increased plaque stability and reduced macrophage infiltration in mice treated with ranolazine. Human patient data supported this finding, as plasma levels of IL-6 and hs-CRP were significantly reduced after ranolazine treatement whereas the control treatment group did not show changes in those inflammatory markers. Mechanistically, we suggest that ranolazine reduces the Na⁺ content of cells leading to an abrogation of inflammation induced Ca²⁺ entry resulting in a massive reduction of inflammation induced adhesion molecules (ICAM, VCAM, and E-SELECTIN) and soluble cytokines (IL-6 and IL-8) in endothelial cells. This reduction of inflammation is linked to reduced activation of the NF-κB pathway. RNAi mediated knockdown of SLC8A1, a sodium calcium exchanger, phenocopied the results obtained with ranolazine.

Conclusions: The presented findings suggest anti-inflammatory effects of ranolazine in a mouse model of atherosclerosis, in human patients and in in vitro experiments. This might be due to a modulation of intracellular Na⁺ levels resulting in a decreased capacity to mount a full response to inflammation.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/reduction-of-intracellular-sodium-protects-from-inflammation-and-atherosclerotic-plaque-progression/