Université de Lorraine, Inserm, Centre d'Investigations Cliniques Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), 5, rue du Morvan, 54500 Vandoeuvre-Les-Nancy, France.
Cardiovascular R&D Centre-UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Alameda Professor Hernâni Monteiro 4200-319 Porto, Portugal.
Eur Heart J. 2022 Dec 21;43(48):4991-5002. doi: 10.1093/eurheartj/ehac495.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.
Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.
Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可改善多种患者人群的心血管结局，但它们的作用机制仍需进一步研究。本研究旨在使用大规模蛋白质组学方法探讨恩格列净对心力衰竭患者循环细胞内蛋白水平的影响。
在 EMPEROR-Reduced 和 EMPEROR-Preserved 两项研究中，1134 例患者在基线、12 周和 52 周时使用 Olink® Explore 1536 平台检测了超过 1250 种循环蛋白。统计和生物信息学分析鉴定了差异表达蛋白（恩格列净与安慰剂相比），并将这些蛋白与心脏和肾脏中已证实的生物学作用相关联。在 12 周时，1283 种蛋白中有 32 种满足差异表达的阈值，即其水平变化≥10%，假发现率<1%（恩格列净与安慰剂相比）。其中，恩格列净对 9 种蛋白的作用最大：胰岛素样生长因子结合蛋白 1、转铁蛋白受体蛋白 1、碳酸酐酶 2、促红细胞生成素、蛋白谷氨酰胺γ-谷氨酰转移酶 2、胸腺素β-10、U 型线粒体肌酸激酶、胰岛素样生长因子结合蛋白 4 和脂肪细胞脂肪酸结合蛋白 4。从基线到 52 周的蛋白变化与从基线到 12 周的变化基本一致，除恩格列净在 52 周时使肾损伤分子-1的水平降低≥10%，而在 12 周时没有。差异表达蛋白最常见的生物学作用似乎是促进心脏、肾脏或内皮细胞中的自噬流，这是 6 种蛋白的特征。差异表达蛋白对心脏的其他作用包括减轻氧化应激、抑制炎症和纤维化，以及增强线粒体健康和能量、修复和再生能力。差异表达蛋白在肾脏中的作用涉及促进自噬、完整性和再生、抑制肾脏炎症和纤维化，以及调节肾脏肾小管钠重吸收。
心力衰竭患者循环蛋白水平的变化与实验研究的结果一致，这些研究表明 SGLT2 抑制剂的作用可能与作用于心脏和肾脏以促进自噬流、营养剥夺信号和跨膜钠转运有关。
