Pérez-Carrillo Lorena, Aragón-Herrera Alana, Giménez-Escamilla Isaac, Delgado-Arija Marta, García-Manzanares María, Anido-Varela Laura, Lago Francisca, Martínez-Dolz Luis, Portolés Manuel, Tarazón Estefanía, Roselló-Lletí Esther
Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), 46026 Valencia, Spain.
Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, 15706 Santiago de Compostela, Spain.
Pharmaceutics. 2022 Sep 21;14(10):1996. doi: 10.3390/pharmaceutics14101996.
Despite the reduction of cardiovascular events, including the risk of death, associated with sodium/glucose cotransporter 2 inhibitors (SGLT2i), their basic action remains unclear. Sodium/hydrogen exchanger (NHE) has been proposed as the mechanism of action, but there are controversies related to its function and expression in heart failure (HF). We hypothesized that sodium transported-related molecules could be altered in HF and modulated through SGLT2i. Transcriptome alterations in genes involved in sodium transport in HF were investigated in human heart samples by RNA-sequencing. NHE11 and NHE1 protein levels were determined by ELISA; the effect of empagliflozin on NHE11 and NHE1 mRNA levels in rats' left ventricular tissues was studied through RT-qPCR. We highlighted the overexpression of and sodium transport genes and the increase of the proteins that encode them (NHE11 and NHE1). NHE11 levels were correlated with left ventricular diameters, so we studied the effect of SGLT2i on its expression, observing that NHE11 mRNA levels were reduced in treated rats. We showed alterations in several sodium transports and reinforced the importance of these channels in HF progression. We described upregulation in NHE11 and NHE1, but only NHE11 correlated with human cardiac dysfunction, and its levels were reduced after treatment with empagliflozin. These results propose NHE11 as a potential target of SGLT2i in cardiac tissue.
尽管钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）可降低心血管事件风险，包括死亡风险，但其基本作用仍不清楚。钠-氢交换体（NHE）被认为是其作用机制，但关于其在心力衰竭（HF）中的功能和表达存在争议。我们推测，与钠转运相关的分子在HF中可能发生改变，并可通过SGLT2i进行调节。通过RNA测序研究了人类心脏样本中HF相关钠转运基因的转录组变化。采用ELISA法测定NHE11和NHE1蛋白水平；通过RT-qPCR研究恩格列净对大鼠左心室组织中NHE11和NHE1 mRNA水平的影响。我们强调了与钠转运相关基因的过表达以及编码这些基因的蛋白质（NHE11和NHE1）的增加。NHE11水平与左心室直径相关，因此我们研究了SGLT2i对其表达的影响，观察到治疗大鼠的NHE11 mRNA水平降低。我们发现几种钠转运存在改变，并强化了这些通道在HF进展中的重要性。我们描述了NHE11和NHE1的上调，但只有NHE11与人类心脏功能障碍相关，并且在恩格列净治疗后其水平降低。这些结果表明NHE11是SGLT2i在心脏组织中的潜在靶点。
