2. Academic Validation
  3. Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2

  • Basic Res Cardiol. 2024 Jul 24. doi: 10.1007/s00395-024-01067-9.
Sha Chen 1,  Qian Wang 1,  Diane Bakker 1,  Xin Hu 1,  Liping Zhang 2,  Ingeborg van der Made 3,  Anna M Tebbens 1,  Csenger Kovácsházi 4,  Zoltán Giricz 4 5,  Gábor B Brenner 4,  Peter Ferdinandy 4 5,  Gert Schaart 6,  Anne Gemmink 6,  Matthijs K C Hesselink 6,  Mathilde R Rivaud 3,  Michael P Pieper 7,  Markus W Hollmann 1,  Nina C Weber 1,  Jean-Luc Balligand 8,  Esther E Creemers 3,  Ruben Coronel 3,  Coert J Zuurbier 9
Affiliations

Affiliations

  • 1 Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, USA.
  • 3 Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • 4 HUN-REN-SU System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089, Budapest, Hungary.
  • 5 Pharmahungary Group, 6722, Szeged, Hungary.
  • 6 Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands.
  • 7 CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
  • 8 Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC) and Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium.
  • 9 Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A.), Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.j.zuurbier@amsterdamumc.nl.
PMID: 39046464 DOI: 10.1007/s00395-024-01067-9
Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO Animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO Animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

Keywords

Diastolic dysfunction; Heart failure; NHE1; Nitric oxide; Oxidative stress; SGLT2 inhibitors.

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