2. Academic Validation
  3. Glycoursodeoxycholic acid 3 sulfate sodium links hemodynamics and bile acid metabolism in aortic stenosis

Glycoursodeoxycholic acid 3 sulfate sodium links hemodynamics and bile acid metabolism in aortic stenosis

  • J Adv Res. 2026 Jun:84:639-655. doi: 10.1016/j.jare.2025.09.011.
Min Zhu 1,  Kun Hua 2,  Huiqing Wang 3,  Zhiyuan Guan 4,  Zexin Tong 5,  Juan Gao 6,  Quanyou Shi 6,  Hu Wang 6,  Shen Yan 7,  Yuhua Liu 2,  Qingqing Shi 8,  Tan Xu 6,  Jiaxing Wang 6,  Tianqi Chang 6,  Yuzhou Xue 6,  Yaobo Zhao 9,  Yiwen Fu 3,  Huiping Zheng 4,  Xinheng Feng 6,  Shaomei Shang 10,  Xiu-Jie Wang 8,  Shi-Qiang Wang 5,  Zhe Zhang 4,  Feng Lan 11,  Changtao Jiang 7,  Xiubin Yang 12,  Lemin Zheng 13,  Ming Xu 14
Affiliations

Affiliations

  • 1 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China; State Key Laboratory of Cardiovascular Disease, Key Laboratory of Pluripotent Stem Cells in Cardiac Repair and Regeneration, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
  • 2 Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 3 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China.
  • 4 Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China.
  • 5 State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
  • 6 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China.
  • 7 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 8 Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 9 Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100050, China.
  • 10 School of Nursing, Peking University, Beijing 100191, China.
  • 11 State Key Laboratory of Cardiovascular Disease, Key Laboratory of Pluripotent Stem Cells in Cardiac Repair and Regeneration, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
  • 12 Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China. Electronic address: [email protected].
  • 13 The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 14 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China. Electronic address: [email protected].
PMID: 40934971 DOI: 10.1016/j.jare.2025.09.011
Abstract

Introduction: Aortic stenosis (AS) involves aortic obstruction, pressure overload, reduced cardiac output, and impaired organ arterial hemodynamics. Many patients remain at risk of rehospitalization or death after transcatheter aortic valve replacement (TAVR) due to unclear mechanisms. Our previous studies linked bile acids (BAs) metabolism to heart-other organ crosstalk, but the BAs-hemodynamics interplay in AS remains unclear.

Objectives: To investigate metabolic abnormalities in AS, focusing on the role of BA metabolism in AS pathogenesis and the underlying mechanisms.

Methods: An acute canine model of AS was established via intra-aortic balloon catheter-induced transverse aortic obstruction (ITAO). Computational fluid dynamics (CFD) simulation was performed to assess the arterial hemodynamics of the aorta and Other organs. Untargeted/targeted metabolomics and transcriptomics were performed in ITAO and deleting ITAO (deITAO) canines. The findings were validated in 33 controls and 30 AS patients. Metabolic predictive performance was assessed by the area under the receiver operating characteristic (AUROC) curve. Transcriptomic and western blot analyses were used to assess the effects of glycoursodeoxycholic acid (GUDCA) and glycoursodeoxycholic acid 3 sulfate sodium (GUDCA-3S) on isoproterenol (ISO)-induced myocardial remodeling.

Results: ITAO replicated AS hemodynamics (reduced cardiac output, increased aortic velocity), reversed post-deITAO. CFD revealed that ITAO increased organ (e.g., liver) artery pressure, improved after deITAO. Untargeted metabolomics identified 1583 differentially abundant metabolites; transcriptomics revealed 291 DEGs enriched in BA biosynthesis. Targeted BA analysis revealed that GUDCA-3S was elevated in ITAO canines, correlated with aortic velocity (R = -0.4822, P = 0.0002) and BNP (R = 0.3836, P = 0.0019) in AS patients, and exhibited superior AS diagnostic performance (AUROC = 0.844, P < 0.001). Reduced aortic flow upregulated hepatic SULT2A1, driving GUDCA sulfonation to GUDCA-3S and weakening GUDCA's cardioprotection by impairing IL-17/NF-κB signaling inhibition in ISO-induced cardiomyocytes.

Conclusions: BA metabolism dysfunction responds to cardiac hemodynamic changes, with GUDCA-3S linking cardiac hemodynamics and BA metabolism in AS.

Keywords

Aortic stenosis; Bile acid metabolism; Cardiac remodeling; Glycoursodeoxycholic acid 3 sulfate sodium; Pressure overload.

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