Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation
Abstract
Aims: Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). Methods and results: The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1α in HFpEF appeared as dimers/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress/eNOS-dependent PKGIα oxidation and polymerization resulting in a higher fraction of PKGIα monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGIα activity in HFpEF increased upon empagliflozin leading to improved phosphorylation of myofilament proteins. In skinned HFpEF cardiomyocytes, empagliflozin improved cardiomyocyte stiffness in an anti-oxidative/PKGIα-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGIα polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients. Conclusion: Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO–sGC–cGMP–cascade and PKGIα activity via reduced PKGIα oxidation and polymerization leading to less pathological cardiomyocyte stiffness.
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- Authors
- Kolijn, D., Pabel, S., Tian, Y., Lódi, M., Herwig, M., Carrizzo, A., Zhazykbayeva, S., Kovács, Á., Fülöp, G. Á., Falcão-Pires, I., Reusch, P. H., Linthout, S. V., Papp, Z., van Heerebeek, L., Vecchione, C., Maier, L. S., Ciccarelli, M., Tschöpe, C., Mügge, A., Bagi, Z., Sossalla, S., & Hamdani, N.
- Affiliations
- St. Josef-Hospital (DE)
- University Hospital Regensburg (DE)
- Augusta University (US)
- University of Debrecen (HU)
- Istituto Neurologico Mediterraneo (IT)
- Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany
- Ruhr University Bochum (DE)
- Department of Surgery and Physiology, University of Porto, Porto, Portugal
- Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany
- Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
- Department of Cardiology, Onze Lieve Vrouw Gasthuis Amsterdam
- University of Salerno (IT)
- Corresponding author
- Hamdani, Nazha
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-05-12
- Volume
- 117
- Issue
- 2
- Pages
- 495-507
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- OpenAlex
- W3024144838
- Cited by
- 323
- References
- 32
- Citations by year
- 2026: 40 · 2025: 50 · 2024: 71 · 2023: 48 · 2022: 69 · 2021: 34 · 2020: 11
- FWCI
- 25.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (HA 7512/2-1, SFB1350, Project A6)
- Else Kröner-Fresenius Stiftung
- German Society of Internal Medicine
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- empagliflozin, heart failure with preserved ejection fraction, SGLT2 inhibitors, endothelial dysfunction, cardiomyocyte stiffness, oxidative stress, endothelial nitric oxide synthase, nitric oxide signaling, cyclic GMP, inflammation, diastolic dysfunction
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Aged, Animals, Anti-Inflammatory Agents, Antioxidants, Benzhydryl Compounds, Disease Models, Animal, Female, Glucosides, Heart Failure, Humans, Male, Middle Aged, Rats, Zucker, Stroke Volume, Signal Transduction, Ventricular Function, Left, Oxidative Stress, Inflammation Mediators, Myocytes, Cardiac, Endothelial Cells, Rats, Cyclic GMP-Dependent Protein Kinase Type I
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