卡格列净对HFpEF大鼠的代谢组学分析及其机制。

Guorui Zhang, Qingjuan Zuo, Sai Ma, Lili He, Zhongli Wang, Jianlong Zhai, Tingting Zhang, Yan Wang, Yifang Guo
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引用次数: 0

摘要

背景:保留射血分数的心力衰竭(HFpEF)是一种具有挑战性的心血管疾病,其特征是收缩功能正常,但舒张功能受损。尽管其发病率越来越高,但治疗选择仍然有限。本研究探讨了钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂canagliflozin对HFpEF心功能和能量代谢的代谢影响。方法:采用Dahl盐敏感大鼠建立HFpEF大鼠模型,并对对照组(a)、HFpEF (B)和卡格列净处理的HFpEF (C)三个实验组进行评价。本研究对心肌结构和功能进行综合分析,代谢组学分析,并详细评估心肌能量代谢,包括线粒体呼吸能力和ATP合成。此外,我们在控制条件下使用H9C2心肌细胞验证了我们的发现。结果:卡格列净治疗可显著改善心脏重构指标,包括心肌体积和纤维化面积减少,同时增强舒张功能(E/A比)。代谢组学分析显示高代谢状态正常化,关键代谢物显著减少,包括l -赖氨酸、d -葡萄糖和尿苷。治疗恢复了多种代谢途径的平衡,特别是影响β-丙氨酸代谢、嘧啶代谢和柠檬酸循环。值得注意的是,卡格列净增强了线粒体呼吸功能,增加了ATP合成,优化了脂肪酸利用,这可以通过降低游离脂肪酸含量来证明。结论:我们的研究结果表明,卡格列净通过多种代谢途径发挥心脏保护作用,这表明它有可能作为HFpEF的治疗选择。该药物优化能量代谢和改善线粒体功能的能力代表了治疗这种具有挑战性的疾病的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.

Background: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.

Methods: We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions.

Results: Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content.

Conclusion: Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

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