Protease XIV abolishes NHE inhibition by empagliflozin in cardiac cells

Frontiers in Physiology

Physiology

Coert J. Zuurbier¹  Sha Chen¹  Ruben Coronel²  Shirley C. M. Van Amersfoorth²  Jan W. T. Fiolet²  Antonius Baartscheer²  Cees A. Schumacher²  Marieke W. Veldkamp² 

[1] Amsterdam UMC, Location AMC, Department of Anaesthesiology, Laboratory of Experimental Intensive Care and Anaesthesiology (L.E.I.C.A.), Amsterdam, Netherlands;Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, Netherlands;Amsterdam UMC, Location AMC, Department of Experimental Cardiology, Amsterdam, Netherlands;Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, Netherlands;

关键词: SGLT2;    NHE;    protease XIV;    empagliflozin;    cardiomyocyte;   

DOI  :  10.3389/fphys.2023.1179131

 received in 2023-03-03, accepted in 2023-07-13,  发布年份 2023

来源: Frontiers

【 摘 要 】

Background: SGLT2i directly inhibit the cardiac sodium-hydrogen exchanger-1 (NHE1) in isolated ventricular cardiomyocytes (CMs). However, other studies with SGLT2i have yielded conflicting results. This may be explained by methodological factors including cell isolation techniques, cell types and ambient pH. In this study, we tested whether the use of protease XIV (PXIV) may abrogate inhibition of SGLT2i on cardiac NHE1 activity in isolated rabbit CMs or rat cardiomyoblast cells (H9c2), in a pH dependent manner.Methods: Rabbit ventricular CMs were enzymatically isolated from Langendorff-perfused hearts during a 30-min perfusion period followed by a 25-min after-dissociation period, using a collagenase mixture without or with a low dose PXIV (0.009 mg/mL) present for different periods. Empagliflozin (EMPA) inhibition on NHE activity was then assessed at pH of 7.0, 7.2 and 7.4. In addition, effects of 10 min PXIV treatment were also evaluated in H9c2 cells for EMPA and cariporide NHE inhibition.Results: EMPA reduced NHE activity in rabbit CMs that were not exposed to PXIV treatment or undergoing a 35-min PXIV treatment, independent of pH levels. However, when exposure time to PXIV was extended to 55 min, NHE inhibition by Empa was completely abolished at all three pH levels. In H9c2 cells, NHE inhibition by EMPA was evident in non-treated cells but lost after 10-min incubation with PXIV. NHE inhibition by cariporide was unaffected by PXIV.Conclusion: The use of protease XIV in cardiac cell isolation procedures obliterates the inhibitory effects of SGLT2i on NHE1 activity in isolated cardiac cells, independent of pH.

【 授权许可】

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Copyright © 2023 Chen, Schumacher, Van Amersfoorth, Fiolet, Baartscheer, Veldkamp, Coronel and Zuurbier.