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...
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| Veröffentlicht in: | Cardiovascular research 2021-01, Vol.117 (2), p.495-507 |
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| creator | Kolijn, Detmar Pabel, Steffen Tian, Yanna Lódi, Mária Herwig, Melissa Carrizzo, Albino Zhazykbayeva, Saltanat Kovács, Árpád Fülöp, Gábor Á Falcão-Pires, Inês Reusch, Peter H Linthout, Sophie Van Papp, Zoltán van Heerebeek, Loek Vecchione, Carmine Maier, Lars S Ciccarelli, Michele Tschöpe, Carsten Mügge, Andreas Bagi, Zsolt Sossalla, Samuel Hamdani, Nazha |
| description | 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. |
| doi_str_mv | 10.1093/cvr/cvaa123 |
| format | Article |
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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.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvaa123</identifier><identifier>PMID: 32396609</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Aged ; Animals ; Anti-Inflammatory Agents - pharmacology ; Antioxidants - pharmacology ; Benzhydryl Compounds - pharmacology ; Cyclic GMP-Dependent Protein Kinase Type I - metabolism ; Disease Models, Animal ; Endothelial Cells - drug effects ; Endothelial Cells - enzymology ; Endothelial Cells - immunology ; Female ; Glucosides - pharmacology ; Heart Failure - drug therapy ; Heart Failure - enzymology ; Heart Failure - immunology ; Heart Failure - physiopathology ; Humans ; Inflammation Mediators - metabolism ; Male ; Middle Aged ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - enzymology ; Myocytes, Cardiac - immunology ; Oxidative Stress - drug effects ; Rats ; Rats, Zucker ; Signal Transduction ; Sodium-Glucose Transporter 2 Inhibitors - pharmacology ; Stroke Volume - drug effects ; Ventricular Function, Left - drug effects</subject><ispartof>Cardiovascular research, 2021-01, Vol.117 (2), p.495-507</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com. 2020</rights><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c357t-2e07079d86fb26e2f912f5df961c627acc93f9ebd67488b0a5eead7f440525463</citedby><cites>FETCH-LOGICAL-c357t-2e07079d86fb26e2f912f5df961c627acc93f9ebd67488b0a5eead7f440525463</cites><orcidid>0000-0003-0528-1748 ; 0000-0002-2473-4565 ; 0000-0003-0374-1325 ; 0000-0001-8755-2980 ; 0000-0002-3053-0008 ; 0000-0003-2379-1960 ; 0000-0001-8034-2673 ; 0000-0003-1937-3782 ; 0000-0002-4675-1542 ; 0000-0002-6533-770X ; 0000-0001-9548-6995 ; 0000-0001-6718-2871</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32396609$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kolijn, Detmar</creatorcontrib><creatorcontrib>Pabel, Steffen</creatorcontrib><creatorcontrib>Tian, Yanna</creatorcontrib><creatorcontrib>Lódi, Mária</creatorcontrib><creatorcontrib>Herwig, Melissa</creatorcontrib><creatorcontrib>Carrizzo, Albino</creatorcontrib><creatorcontrib>Zhazykbayeva, Saltanat</creatorcontrib><creatorcontrib>Kovács, Árpád</creatorcontrib><creatorcontrib>Fülöp, Gábor Á</creatorcontrib><creatorcontrib>Falcão-Pires, Inês</creatorcontrib><creatorcontrib>Reusch, Peter H</creatorcontrib><creatorcontrib>Linthout, Sophie Van</creatorcontrib><creatorcontrib>Papp, Zoltán</creatorcontrib><creatorcontrib>van Heerebeek, Loek</creatorcontrib><creatorcontrib>Vecchione, Carmine</creatorcontrib><creatorcontrib>Maier, Lars S</creatorcontrib><creatorcontrib>Ciccarelli, Michele</creatorcontrib><creatorcontrib>Tschöpe, Carsten</creatorcontrib><creatorcontrib>Mügge, Andreas</creatorcontrib><creatorcontrib>Bagi, Zsolt</creatorcontrib><creatorcontrib>Sossalla, Samuel</creatorcontrib><creatorcontrib>Hamdani, Nazha</creatorcontrib><title>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</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>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.</description><subject>Aged</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antioxidants - pharmacology</subject><subject>Benzhydryl Compounds - pharmacology</subject><subject>Cyclic GMP-Dependent Protein Kinase Type I - metabolism</subject><subject>Disease Models, Animal</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - enzymology</subject><subject>Endothelial Cells - immunology</subject><subject>Female</subject><subject>Glucosides - pharmacology</subject><subject>Heart Failure - drug therapy</subject><subject>Heart Failure - enzymology</subject><subject>Heart Failure - immunology</subject><subject>Heart Failure - physiopathology</subject><subject>Humans</subject><subject>Inflammation Mediators - metabolism</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Myocytes, Cardiac - immunology</subject><subject>Oxidative Stress - drug effects</subject><subject>Rats</subject><subject>Rats, Zucker</subject><subject>Signal Transduction</subject><subject>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</subject><subject>Stroke Volume - drug effects</subject><subject>Ventricular Function, Left - drug effects</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhxB35hJCqgGPHzuaIqlKQKnGBczRrj1kXJw62kxKehlfgFXrhxjNhugtHDuOx5W_-f6SfkKc1e1mzTrzSSywFUHNxj2zqVspK8EbeJxvG2LZSQokT8iil6_KUsm0ekhPBRacU6zbk58UwwSfvrA_f3EjdMMWwYKI4mpD36B14CqOhGqJxYViDXjNSO486uzDefi8z-3mAciLETC04P0ekNy7v6RQxYVzQULzGO57aCIfL4oBGNLMuv8WycqP1MAyQQ1yr8NUZyG5BOkHe38Ca7nYoXMZi-NmNkJBe_vpBj2QYH5MHFnzCJ8d-Sj6-ufhw_ra6en_57vz1VaWFbHPFkbWs7cxW2R1XyG1XcyuN7VStFW9B607YDndGtc12u2MgEcG0tmmY5LJR4pS8OOiWZb7MmHI_uKTRexgxzKnnDeMNl50UBT07oDqGlCLafopugLj2Nev_JNeX5PpjcoV-dhSedwOaf-zfqArw_ACEefqv0m-Hu6tH</recordid><startdate>20210121</startdate><enddate>20210121</enddate><creator>Kolijn, Detmar</creator><creator>Pabel, Steffen</creator><creator>Tian, Yanna</creator><creator>Lódi, Mária</creator><creator>Herwig, Melissa</creator><creator>Carrizzo, Albino</creator><creator>Zhazykbayeva, Saltanat</creator><creator>Kovács, Árpád</creator><creator>Fülöp, Gábor Á</creator><creator>Falcão-Pires, Inês</creator><creator>Reusch, Peter H</creator><creator>Linthout, Sophie Van</creator><creator>Papp, Zoltán</creator><creator>van Heerebeek, Loek</creator><creator>Vecchione, Carmine</creator><creator>Maier, Lars S</creator><creator>Ciccarelli, Michele</creator><creator>Tschöpe, Carsten</creator><creator>Mügge, Andreas</creator><creator>Bagi, Zsolt</creator><creator>Sossalla, Samuel</creator><creator>Hamdani, Nazha</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0528-1748</orcidid><orcidid>https://orcid.org/0000-0002-2473-4565</orcidid><orcidid>https://orcid.org/0000-0003-0374-1325</orcidid><orcidid>https://orcid.org/0000-0001-8755-2980</orcidid><orcidid>https://orcid.org/0000-0002-3053-0008</orcidid><orcidid>https://orcid.org/0000-0003-2379-1960</orcidid><orcidid>https://orcid.org/0000-0001-8034-2673</orcidid><orcidid>https://orcid.org/0000-0003-1937-3782</orcidid><orcidid>https://orcid.org/0000-0002-4675-1542</orcidid><orcidid>https://orcid.org/0000-0002-6533-770X</orcidid><orcidid>https://orcid.org/0000-0001-9548-6995</orcidid><orcidid>https://orcid.org/0000-0001-6718-2871</orcidid></search><sort><creationdate>20210121</creationdate><title>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</title><author>Kolijn, Detmar ; Pabel, Steffen ; Tian, Yanna ; Lódi, Mária ; Herwig, Melissa ; Carrizzo, Albino ; Zhazykbayeva, Saltanat ; Kovács, Árpád ; Fülöp, Gábor Á ; Falcão-Pires, Inês ; Reusch, Peter H ; Linthout, Sophie Van ; Papp, Zoltán ; van Heerebeek, Loek ; Vecchione, Carmine ; Maier, Lars S ; Ciccarelli, Michele ; Tschöpe, Carsten ; Mügge, Andreas ; Bagi, Zsolt ; Sossalla, Samuel ; Hamdani, Nazha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c357t-2e07079d86fb26e2f912f5df961c627acc93f9ebd67488b0a5eead7f440525463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aged</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Antioxidants - pharmacology</topic><topic>Benzhydryl Compounds - pharmacology</topic><topic>Cyclic GMP-Dependent Protein Kinase Type I - metabolism</topic><topic>Disease Models, Animal</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - enzymology</topic><topic>Endothelial Cells - immunology</topic><topic>Female</topic><topic>Glucosides - pharmacology</topic><topic>Heart Failure - drug therapy</topic><topic>Heart Failure - enzymology</topic><topic>Heart Failure - immunology</topic><topic>Heart Failure - physiopathology</topic><topic>Humans</topic><topic>Inflammation Mediators - metabolism</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Myocytes, Cardiac - immunology</topic><topic>Oxidative Stress - drug effects</topic><topic>Rats</topic><topic>Rats, Zucker</topic><topic>Signal Transduction</topic><topic>Sodium-Glucose Transporter 2 Inhibitors - pharmacology</topic><topic>Stroke Volume - drug effects</topic><topic>Ventricular Function, Left - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kolijn, Detmar</creatorcontrib><creatorcontrib>Pabel, Steffen</creatorcontrib><creatorcontrib>Tian, Yanna</creatorcontrib><creatorcontrib>Lódi, Mária</creatorcontrib><creatorcontrib>Herwig, Melissa</creatorcontrib><creatorcontrib>Carrizzo, Albino</creatorcontrib><creatorcontrib>Zhazykbayeva, Saltanat</creatorcontrib><creatorcontrib>Kovács, Árpád</creatorcontrib><creatorcontrib>Fülöp, Gábor Á</creatorcontrib><creatorcontrib>Falcão-Pires, Inês</creatorcontrib><creatorcontrib>Reusch, Peter H</creatorcontrib><creatorcontrib>Linthout, Sophie Van</creatorcontrib><creatorcontrib>Papp, Zoltán</creatorcontrib><creatorcontrib>van Heerebeek, Loek</creatorcontrib><creatorcontrib>Vecchione, Carmine</creatorcontrib><creatorcontrib>Maier, Lars S</creatorcontrib><creatorcontrib>Ciccarelli, Michele</creatorcontrib><creatorcontrib>Tschöpe, Carsten</creatorcontrib><creatorcontrib>Mügge, Andreas</creatorcontrib><creatorcontrib>Bagi, Zsolt</creatorcontrib><creatorcontrib>Sossalla, Samuel</creatorcontrib><creatorcontrib>Hamdani, Nazha</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kolijn, Detmar</au><au>Pabel, Steffen</au><au>Tian, Yanna</au><au>Lódi, Mária</au><au>Herwig, Melissa</au><au>Carrizzo, Albino</au><au>Zhazykbayeva, Saltanat</au><au>Kovács, Árpád</au><au>Fülöp, Gábor Á</au><au>Falcão-Pires, Inês</au><au>Reusch, Peter H</au><au>Linthout, Sophie Van</au><au>Papp, Zoltán</au><au>van Heerebeek, Loek</au><au>Vecchione, Carmine</au><au>Maier, Lars S</au><au>Ciccarelli, Michele</au><au>Tschöpe, Carsten</au><au>Mügge, Andreas</au><au>Bagi, Zsolt</au><au>Sossalla, Samuel</au><au>Hamdani, Nazha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2021-01-21</date><risdate>2021</risdate><volume>117</volume><issue>2</issue><spage>495</spage><epage>507</epage><pages>495-507</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>32396609</pmid><doi>10.1093/cvr/cvaa123</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-0528-1748</orcidid><orcidid>https://orcid.org/0000-0002-2473-4565</orcidid><orcidid>https://orcid.org/0000-0003-0374-1325</orcidid><orcidid>https://orcid.org/0000-0001-8755-2980</orcidid><orcidid>https://orcid.org/0000-0002-3053-0008</orcidid><orcidid>https://orcid.org/0000-0003-2379-1960</orcidid><orcidid>https://orcid.org/0000-0001-8034-2673</orcidid><orcidid>https://orcid.org/0000-0003-1937-3782</orcidid><orcidid>https://orcid.org/0000-0002-4675-1542</orcidid><orcidid>https://orcid.org/0000-0002-6533-770X</orcidid><orcidid>https://orcid.org/0000-0001-9548-6995</orcidid><orcidid>https://orcid.org/0000-0001-6718-2871</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cardiovascular research, 2021-01, Vol.117 (2), p.495-507 |
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| recordid | cdi_proquest_miscellaneous_2402425953 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Aged Animals Anti-Inflammatory Agents - pharmacology Antioxidants - pharmacology Benzhydryl Compounds - pharmacology Cyclic GMP-Dependent Protein Kinase Type I - metabolism Disease Models, Animal Endothelial Cells - drug effects Endothelial Cells - enzymology Endothelial Cells - immunology Female Glucosides - pharmacology Heart Failure - drug therapy Heart Failure - enzymology Heart Failure - immunology Heart Failure - physiopathology Humans Inflammation Mediators - metabolism Male Middle Aged Myocytes, Cardiac - drug effects Myocytes, Cardiac - enzymology Myocytes, Cardiac - immunology Oxidative Stress - drug effects Rats Rats, Zucker Signal Transduction Sodium-Glucose Transporter 2 Inhibitors - pharmacology Stroke Volume - drug effects Ventricular Function, Left - drug effects |
| title | 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 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T05%3A26%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Empagliflozin%20improves%20endothelial%20and%20cardiomyocyte%20function%C2%A0in%20human%20heart%20failure%20with%20preserved%20ejection%20fraction%20via%20reduced%20pro-inflammatory-oxidative%20pathways%20and%20protein%20kinase%20G%CE%B1%20oxidation&rft.jtitle=Cardiovascular%20research&rft.au=Kolijn,%20Detmar&rft.date=2021-01-21&rft.volume=117&rft.issue=2&rft.spage=495&rft.epage=507&rft.pages=495-507&rft.issn=0008-6363&rft.eissn=1755-3245&rft_id=info:doi/10.1093/cvr/cvaa123&rft_dat=%3Cproquest_cross%3E2402425953%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2402425953&rft_id=info:pmid/32396609&rft_oup_id=10.1093/cvr/cvaa123&rfr_iscdi=true |