Detmar Kolijn1,2,3, Steffen Pabel4, Yanna Tian5, Mária Lódi1,3,6, Melissa Herwig1,2,3, Albino Carrizzo7, Saltanat Zhazykbayeva1,2,3, Árpád Kovács1,2, Gábor Á Fülöp1, Inês Falcão-Pires8, Peter H Reusch9, Sophie Van Linthout10,11,12, Zoltán Papp6, Loek van Heerebeek13, Carmine Vecchione7,14, Lars S Maier4, Michele Ciccarelli14, Carsten Tschöpe10,11,12, Andreas Mügge1,2, Zsolt Bagi5, Samuel Sossalla4,15,16, Nazha Hamdani1,2,3,9. 1. Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany. 2. Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany. 3. Institute of Physiology, Ruhr University Bochum, Bochum, Germany. 4. Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. 5. Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA. 6. Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. 7. Vascular Pathophysiology Unit - I.R.C.C.S. Neuromed, 86077, Pozzilli (IS), Italy. 8. Department of Surgery and Physiology, University of Porto, Porto, Portugal. 9. Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany. 10. Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany. 11. Department of Cardiology and Pneumology, Charité, University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany. 12. German Center for Cardiovascular Research (DZHK), partner site, Berlin, Germany. 13. Department of Cardiology, Onze Lieve Vrouw Gasthuis Amsterdam. 14. Department of Medicine Surgery and Dentistry - University of Salerno, 84081, Baronissi (SA), Italy. 15. Clinic for Cardiology & Pneumology, Georg-August University Goettingen. 16. DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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