{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T05:07:54Z","timestamp":1776488874990,"version":"3.51.2"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T00:00:00Z","timestamp":1589241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HA 7512\/2-1"],"award-info":[{"award-number":["HA 7512\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius Stiftung","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"crossref"}]},{"name":"German Society of Internal Medicine"},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1350"],"award-info":[{"award-number":["SFB1350"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Project A6"],"award-info":[{"award-number":["Project A6"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>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).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>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-\u03b1, 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 PKGI\u03b1 oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1\u03b1 in HFpEF appeared as dimers\/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress\/eNOS-dependent PKGI\u03b1 oxidation and polymerization resulting in a higher fraction of PKGI\u03b1 monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGI\u03b1 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\/PKGI\u03b1-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGI\u03b1 polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO\u2013sGC\u2013cGMP\u2013cascade and PKGI\u03b1 activity via reduced PKGI\u03b1 oxidation and polymerization leading to less pathological cardiomyocyte stiffness.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa123","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T11:29:14Z","timestamp":1588764554000},"page":"495-507","source":"Crossref","is-referenced-by-count":282,"title":["Empagliflozin improves endothelial and cardiomyocyte function\u00a0in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase G\u03b1 oxidation"],"prefix":"10.1093","volume":"117","author":[{"given":"Detmar","family":"Kolijn","sequence":"first","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Physiology, Ruhr University Bochum, Bochum, Germany"}]},{"given":"Steffen","family":"Pabel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0374-1325","authenticated-orcid":false,"given":"Yanna","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6533-770X","authenticated-orcid":false,"given":"M\u00e1ria","family":"L\u00f3di","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Physiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}]},{"given":"Melissa","family":"Herwig","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Physiology, Ruhr University Bochum, Bochum, Germany"}]},{"given":"Albino","family":"Carrizzo","sequence":"additional","affiliation":[{"name":"Vascular Pathophysiology Unit - I.R.C.C.S. Neuromed, 86077, Pozzilli (IS), Italy"}]},{"given":"Saltanat","family":"Zhazykbayeva","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Physiology, Ruhr University Bochum, Bochum, Germany"}]},{"given":"\u00c1rp\u00e1d","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-1748","authenticated-orcid":false,"given":"G\u00e1bor \u00c1","family":"F\u00fcl\u00f6p","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1937-3782","authenticated-orcid":false,"given":"In\u00eas","family":"Falc\u00e3o-Pires","sequence":"additional","affiliation":[{"name":"Department of Surgery and Physiology, University of Porto, Porto, Portugal"}]},{"given":"Peter H","family":"Reusch","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany"}]},{"given":"Sophie Van","family":"Linthout","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit\u00e9, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany"},{"name":"Department of Cardiology and Pneumology, Charit\u00e9, University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), partner site, Berlin, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-1542","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6718-2871","authenticated-orcid":false,"given":"Loek","family":"van Heerebeek","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Onze Lieve Vrouw Gasthuis Amsterdam"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-4565","authenticated-orcid":false,"given":"Carmine","family":"Vecchione","sequence":"additional","affiliation":[{"name":"Vascular Pathophysiology Unit - I.R.C.C.S. Neuromed, 86077, Pozzilli (IS), Italy"},{"name":"Department of Medicine Surgery and Dentistry - University of Salerno, 84081, Baronissi (SA), Italy"}]},{"given":"Lars S","family":"Maier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-1960","authenticated-orcid":false,"given":"Michele","family":"Ciccarelli","sequence":"additional","affiliation":[{"name":"Department of Medicine Surgery and Dentistry - University of Salerno, 84081, Baronissi (SA), Italy"}]},{"given":"Carsten","family":"Tsch\u00f6pe","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charit\u00e9, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany"},{"name":"Department of Cardiology and Pneumology, Charit\u00e9, University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), partner site, Berlin, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9548-6995","authenticated-orcid":false,"given":"Andreas","family":"M\u00fcgge","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8755-2980","authenticated-orcid":false,"given":"Zsolt","family":"Bagi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8034-2673","authenticated-orcid":false,"given":"Samuel","family":"Sossalla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany"},{"name":"Clinic for Cardiology & Pneumology, Georg-August University Goettingen"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3053-0008","authenticated-orcid":false,"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany"},{"name":"Institute of Physiology, Ruhr University Bochum, Bochum, Germany"},{"name":"Department of Clinical Pharmacology, Ruhr University Bochum, Bochum, Germany"}]}],"member":"286","published-online":{"date-parts":[[2020,5,12]]},"reference":[{"key":"2021022712415130000_cvaa123-B1","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 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