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Pharmacologic modulation of intracellular Na⁺ concentration with ranolazine impacts inflammatory response in humans and mice.

ABSTRACT: Changes in Ca2⁺ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca²⁺ 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⁺-Ca²⁺ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

SUBMITTER: Lenz M

PROVIDER: S-EPMC9303949 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Lenz Max M Salzmann Manuel M Ciotu Cosmin I CI Kaun Christoph C Krychtiuk Konstantin A KA Rehberger Likozar Andreja A Sebestjen Miran M Goederle Laura L Rauscher Sabine S Krivaja Zoriza Z Binder Christoph J CJ Huber Kurt K Hengstenberg Christian C Podesser Bruno K BK Fischer Michael J M MJM Wojta Johann J Hohensinner Philipp J PJ Speidl Walter S WS

Proceedings of the National Academy of Sciences of the United States of America 20220713 29

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ 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 r ...[more]

PMID: 35858345

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Project description:Hydrogen peroxide (H2O2) production in the renal outer medulla is an important determinant of renal medullary blood flow and blood pressure (BP) salt-sensitivity in Dahl salt-sensitive (SS) rats. The mechanisms and pathways responsible for these actions are poorly understood. Recently, we have discovered that the mTOR complex 2 (mTORC2) plays a critical role in BP salt-sensitivity of SS rats by regulating Na+ homeostasis. PP242, an inhibitor of mTORC1/2 pathways exhibits potent natriuretic actions and completely prevented salt-induced hypertension in SS rats. In the present study, we have found that chronic infusion of H2O2 into the single remaining kidney of Sprague Dawley (SD) rats (3 days) stimulated the functional marker (pAKTSer473/AKT) of mTORC2 activity measured by Western Blot analysis. No changes in mTORC1 activity in OM were observed as determined by pS6Ser235/236/S6. Using fluorescent microscopy and the Na+ sensitive dye Sodium Green, we have shown that H2O2 (100 µM added in the bath) increased intracellular sodium concentration ([Na+]i) in renal medullary thick ascending limbs (mTALs) isolated from SD rats. These responses were almost completely abolished by pretreatment of mTAL with 10 µM PP242, indicating that mTORC1/2 pathways were involved in the H2O2 induced increase of [Na+]i. mTAL cell volume remained unchanged (± 1%) by H2O2 as determined by 3D reconstruction confocal laser scanning microscopy techniques. Consistent with the microscopy data, Western Blot analysis of proteins obtained from freshly isolated mTAL treated with 100 µM H2O2 exhibited increased activity/phosphorylation of AKT (pAKTSer473/AKT) that was inhibited by PP242. This was associated with increased protein activity of the apical membrane cotransporter Na+-K+-2Cl- (NKCC2) and the Na/H exchanger (NHE-3). Na+-K+-ATPase activity was increased as reflected an increase in the ratio of pNa+-K+-ATPaseSer16 to total Na+-K+-ATPase. Overall, the results indicate that H2O2 mediated activation of mTORC2 plays a key role in transducing the observed increases of cytosolic [Na+]i despite associated increases of basolateral pump activity.

Dataset Information

Pharmacologic modulation of intracellular Na⁺ concentration with ranolazine impacts inflammatory response in humans and mice.

Publications

Pharmacologic modulation of intracellular Na<sup>+</sup> concentration with ranolazine impacts inflammatory response in humans and mice.

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