Empagliflozin Improves Mitochondrial Biogenesis and Ameliorates Experimental Pulmonary Vascular Remodeling, But May Not Benefit Patients with Pulmonary Arterial Hypertension

恩帕吉菲 心脏病学 医学 肺动脉高压 内科学 线粒体生物发生 生物发生 线粒体 化学 生物 内分泌学 糖尿病 细胞生物学 2型糖尿病 生物化学 基因
作者
Keimei Yoshida,Eszter Tóth,Erik Duijvelaar,Beau Neep,Stuti Agarwal,Xiaoke Pan,Takayuki Jujo,Yu Yoshida,Jurjan Aman,Vinicio de Jesús Pérez,M. Louis Handoko,Frances S. de Man,Sun Xiao-qing,Harm Jan Bogaard
出处
期刊:Cold Spring Harbor Laboratory - medRxiv
标识
DOI:10.1101/2025.01.27.25321226
摘要

Background: The sodium glucose cotransporter 2 (SGLT2) inhibitor may improve mitochondrial biogenesis and attenuate pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). We investigated the impact of empagliflozin in PAH. Methods: Lung sections and primary cell cultures isolated from microvascular endothelial cells (MVECs) were collected from control subjects and PAH patients. MVECs were treated with empagliflozin and mitochondrial biogenesis, cell metabolism, oxidative stress and cell proliferation were evaluated. Subsequently, PAH was induced in male and female rats (n=12 respectively) with SU5416 injection (25 mg/kg s.c.) followed by 3 weeks of hypoxia (10% O2), the experimental PAH model known to mimic human PAH pathophysiology. Four weeks after SU5416 injection, rats were treated by empagliflozin (300 mg/kg chow, n=12) or placebo (n=12) for 4 weeks and hemodynamic, protein and histological analyses were performed. In addition, we conducted a phase IIa proof of concept trial, EMPHOWER, to assess the feasibility of 12 weeks of empagliflozin treatment in PAH patients. Results: Immunofluorescent staining of human lung tissue showed expression of SGLT2 in the intima of small pulmonary arteries from PAH patients, not controls. In comparison to control MVECs, PAH MVECs showed increased protein expression of SGLT2, along with decreased expression of the peroxisome proliferator-activated receptor gamma coactivator-1α. Furthermore, empagliflozin enhanced expression of mitochondrial encoded genes and mitochondrial respiration, suggesting increased mitochondrial biogenesis. Moreover, empagliflozin significantly attenuated oxidative stress and proliferation of PAH MVECs. In SuHx rats, chronic treatment with empagliflozin significantly reduced pulmonary vascular resistance and thickening of the intima of small pulmonary arteries. Finally, 8 patients diagnosed with idiopathic and heritable PAH were enrolled in the phase IIa EMPHOWER trial. There was no discontinuation of empagliflozin during the study period and there were no treatment associated serious adverse events. There were no changes in biomarkers, WHO functional class, six-minute walk distance, or EMPHASIS score. However, RV ejection fraction and RV global longitudinal strain slightly worsened after empagliflozin treatment (from 45 ± 10% to 38 ± 12%, P=0.036, and from -15.2 ± 4.2% to -13.2 ± 3.96%, P=0.002, respectively). Conclusion: SGLT2 expression is increased in the PAH endothelium. Treatment with empagliflozin improves mitochondrial biogenesis and attenuates proliferation of PAH MVECs. Empagliflozin attenuates pulmonary vascular remodeling in experimental PAH. While twelve weeks of empagliflozin treatment seemed feasible in patients with idiopathic or hereditary PAH, we observed signs of RV deterioration.

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