Title:Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism
Volume: 26
Issue: 1
Author(s): Guorui Zhang*, Qingjuan Zuo, Sai Ma, Lili He, Zhongli Wang, Jianlong Zhai, Tingting Zhang, Yan Wang and Yifang Guo*
Affiliation:
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Cardiology, The Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
Keywords:
Canagliflozin, hypertension, HFpEF, metabonomics, H9C2 cardiomyocytes, energy metabolism.
Abstract:
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.
