Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.
Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany.
Cardiovasc Res. 2021 Jan 21;117(2):495-507. doi: 10.1093/cvr/cvaa123.
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).
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.
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.
钠-葡萄糖共转运蛋白 2 抑制剂显示出有利的心血管结局，但潜在机制仍不清楚。本研究旨在探讨恩格列净在人射血分数保留心力衰竭（HFpEF）和鼠 ZDF 肥胖大鼠中的作用机制。
在 HFpEF 患者的人类心肌组织和体内治疗的鼠 ZDF 肥胖大鼠中，研究了恩格列净的急性作用机制。免疫印迹和 ELISA 结果显示，恩格列净显著抑制人源和鼠源 HFpEF 心肌中 ICAM-1、VCAM-1、TNF-α 和 IL-6 水平的升高，并减轻心肌细胞胞质和线粒体中病理氧化参数（H2O2、3-硝基酪氨酸、GSH、脂质过氧化物），同时改善内皮血管舒张功能。在 HFpEF 中，我们发现氧化应激依赖性 eNOS 激活导致 PKGIα 氧化。有趣的是，免疫荧光成像和电子显微镜显示，HFpEF 中氧化的 PKG1α 呈二聚体/聚合物形式，定位于心肌细胞膜外。恩格列净降低氧化应激/依赖于 eNOS 的 PKGIα 氧化和聚合，导致 PKGIα 单体比例增加，从而向胞质内转位。因此，HFpEF 中 NO 水平、sGC 活性、cGMP 浓度和 PKGIα 活性降低，导致肌球蛋白蛋白磷酸化增加。在 HFpEF 的去神经心肌细胞中，恩格列净以抗氧化/PGKIα 依赖性方式改善心肌细胞僵硬。单变量线性回归分析证实了氧化应激和 PKGIα 聚合与 HFpEF 患者心肌细胞僵硬增加和舒张功能障碍的相关性。
恩格列净降低 HFpEF 中的炎症和氧化应激，从而改善 NO-sGC-cGMP 级联和 PKGIα 活性，减少 PKGIα 氧化和聚合，导致病理性心肌细胞僵硬减少。
