Sha Chen, Qian Wang, Diane Bakker, Xin Hu, Liping Zhang, Ingeborg van der Made, Anna M Tebbens, Csenger Kovácsházi, Zoltán Giricz, Gábor B Brenner, Peter Ferdinandy, Gert Schaart, Anne Gemmink, Matthijs K C Hesselink, Mathilde R Rivaud, Michael P Pieper, Markus W Hollmann, Nina C Weber, Jean-Luc Balligand, Esther E Creemers, Ruben Coronel, Coert J Zuurbier
{"title":"Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2.","authors":"Sha Chen, Qian Wang, Diane Bakker, Xin Hu, Liping Zhang, Ingeborg van der Made, Anna M Tebbens, Csenger Kovácsházi, Zoltán Giricz, Gábor B Brenner, Peter Ferdinandy, Gert Schaart, Anne Gemmink, Matthijs K C Hesselink, Mathilde R Rivaud, Michael P Pieper, Markus W Hollmann, Nina C Weber, Jean-Luc Balligand, Esther E Creemers, Ruben Coronel, Coert J Zuurbier","doi":"10.1007/s00395-024-01067-9","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Basic Research in Cardiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00395-024-01067-9","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards.
Basic Research in Cardiology regularly receives articles from the fields of
- Molecular and Cellular Biology
- Biochemistry
- Biophysics
- Pharmacology
- Physiology and Pathology
- Clinical Cardiology