Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Basic Research in Cardiology Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI:10.1007/s00395-024-01067-9
Sha Chen, Qian Wang, Diane Bakker, Xin Hu, Liping Zhang, Ingeborg van der Made, Anna M Tebbens, Csenger Kovácsházi, Zoltán Giricz, Gábor B Brenner, Peter Ferdinandy, Gert Schaart, Anne Gemmink, Matthijs K C Hesselink, Mathilde R Rivaud, Michael P Pieper, Markus W Hollmann, Nina C Weber, Jean-Luc Balligand, Esther E Creemers, Ruben Coronel, Coert J Zuurbier
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引用次数: 0

Abstract

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.

Abstract Image

Empagliflozin 通过抑制 NHE1-NO 通路预防心力衰竭,与 SGLT2 无关。
葡萄糖钠共转运体 2 抑制剂(SGLT2i)是唯一能持续预防或减轻人类心力衰竭(HF)的药物,与射血分数无关。我们早些时候曾提出,SGLT2i Empagliflozin(EMPA)的保护机制是通过减少钠氢交换器 1(NHE1)-一氧化氮(NO)途径介导的,与 SGLT2 无关。在此,我们研究了 SGLT2、NHE1 和 NO 在小鼠 TAC/DOCA 高频模型中的作用。SGLT2 基因敲除小鼠仅表现出收缩功能障碍的减弱,而对其他心房颤动症状没有影响。EMPA可防止收缩和舒张功能障碍、肥大、纤维化、Nppa/Nppb mRNA表达增加以及肺/肝水肿。此外,在WT和SGLT2 KO动物中,EMPA在同等程度上防止了氧化应激、钠钙交换表达和钙/钙调蛋白依赖性蛋白激酶II激活的增加。特别是,虽然未经治疗的高频离体心肌细胞中的 NHE1 活性增加,但 EMPA 治疗阻止了这一现象。由于 EMPA 的保护作用并不需要 SGLT2,因此在 SGLT2 KO 动物中进一步探索了 NHE1 和 NO 之间的通路。使用特异性 NHE1 抑制剂卡利波利(Cariporide)进行体内治疗可模拟 EMPA 的保护作用,但 EMPA 并不提供额外保护。另一方面,用 L-NAME 在体内抑制 NOS 会恶化 HF 并阻止 EMPA 的保护作用。总之,这些数据支持在 TAC/DOCA 诱导的心衰中,EMPA 的有益作用是通过 NHE1-NO 途径介导的,而不是通过 SGLT2 抑制。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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