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

作者：Detmar Kolijn, Steffen Pabel, Yanna Tian, Mária Lódi, Melissa Herwig, Albino Carrizzo, Saltanat Zhazykbayeva, Árṕad Kov́acs, Gábor Áron Fülöp, Inês Falcão‐Pires, Peter Reusch, Sophie Van Linthout, Zoltán Papp, Loek van Heerebeek, Carmine Vecchione, Lars S. Maier, Michele Ciccarelli, Carsten Tschöpe, Andreas Mügge, Zsolt Bagi, Samuel Sossalla, Nazha Hamdani · 发表于：Cardiovascular Research · 年份：2020 · DOI：10.1093/cvr/cvaa123 · 被引用次数：325 · 研究领域：Diabetes Treatment and Management、Cardiovascular Function and Risk Factors、Hyperglycemia and glycemic control in critically ill and hospitalized patients

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, empagli...