Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1
9 affiliations
- 1Burdon Sanderson Cardiac Science Centre and BHF Centre of Research Excellence, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- 2Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, 450000 China
- 3Ningbo No.2 Hospital, Wenzhou Medical University, No.41, Xibei Street, Ningbo, Zhejiang China
- 4Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- 5Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193 China
- 6Ellison Institute of Technology, Winchester House, Heatley Road, The Oxford Science Park, Littlemore, Oxford UK
- 7Single-Molecule Biology Core Lab, Institute of Cellular and Organismic Biology (ICOB), Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115 Taiwan
- 8Department of Public Health and Clinical Medicine, Faculty of Medicine, Umeå University, Umeå, Sweden
- 9CAMS Oxford Institute, Peking Union Medical College, Chinese Academy of Medical Sciences, University of Oxford, Oxford, UK
Abstract
Background: Diabetic cardiomyopathy (DCM) represents a distinct form of heart failure occurring independently of coronary artery disease, yet effective treatments remain limited. While cAMP signaling alterations have been reported in diabetic hearts, the compartment-specific consequences across distinct subcellular pools remain poorly understood. We investigated cytosolic and mitochondrial cAMP microdomain dysfunction in DCM, focusing on ADCY2 and PDE4DIP as potential regulators, and evaluated fibroblast growth factor 1 (FGF1) as a therapeutic intervention using integrated two-dimensional (2D) and three-dimensional (3D) human induced pluripotent stem cell (hiPSC)-derived cardiac models.
Methods: Healthy hiPSC-derived cardiomyocytes were exposed to a diabetic-like environment (high glucose, endothelin-1 and cortisol) in 2D and 3D culture. Two-dimensional studies included bulk RNA sequencing, FRET-based cAMP measurements in cytosolic and mitochondrial outer membrane compartments, and microelectrode array electrophysiology. Three-dimensional cardiac microtissues were assessed by optical mapping to characterize spatial calcium dynamics and conduction properties.
Results: DCM exhibited compartment-specific cAMP dysregulation associated with ADCY2 downregulation and PDE4DIP upregulation. Cytosolic compartments showed preserved baseline cAMP but attenuated forskolin responsiveness, while the mitochondrial outer membrane displayed both reduced baseline cAMP and impaired stimulated responses. Transcriptomic analysis revealed transcriptional signatures consistent with metabolic remodeling, including upregulated fatty acid oxidation machinery, Complex I dysfunction, and elevated phospholamban and CASQ2 expression. 3D optical mapping demonstrated reduced calcium transient amplitude, prolonged transient duration, and severely impaired calcium propagation velocity. FGF1 treatment normalized PDE4DIP expression and restored cAMP dynamics in 2D cultures and partially improved calcium transient amplitude in 3D microtissues, though conduction defects persisted.
Conclusions: Compartment-specific impairment of cAMP microdomains is associated with DCM pathogenesis. Integrated 2D–3D assessment reveals that FGF1 improves cAMP signaling but does not fully reverse metabolic, electrophysiological, or structural abnormalities, highlighting the need for combination therapies targeting both cAMP pathway integrity and conduction restoration.
Graphical abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12933-026-03288-9.
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BibTeX
@article{liu2026compartmentspecific,
title = {{Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1}},
author = {Kun Liu and Kazuki Osuka and Mengying Xu and Rhea Takhar and Neda Mohammadi and Adam Trevett and Jinyan Zhong and Ching-Wen Chang and Nan Wang and Xinyu Hu and Ruirui Dong and Shunan Zhang and YoonYoung Choi and Thamali Ayagama and Mingyu Li and Linna Zhou and Che-Mai Chang and Wan-Chen Huang and Wei-Chiao Chang and Neil Herring and Annika Winbo and Guoliang Hao and Jie Zhang and Dan Li},
journal = {Cardiovascular Diabetology},
year = {2026},
month = jul,
doi = {10.1186/s12933-026-03288-9},
url = {https://doi.org/10.1186/s12933-026-03288-9},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1
AU - Kun Liu
AU - Kazuki Osuka
AU - Mengying Xu
AU - Rhea Takhar
AU - Neda Mohammadi
AU - Adam Trevett
AU - Jinyan Zhong
AU - Ching-Wen Chang
AU - Nan Wang
AU - Xinyu Hu
AU - Ruirui Dong
AU - Shunan Zhang
AU - YoonYoung Choi
AU - Thamali Ayagama
AU - Mingyu Li
AU - Linna Zhou
AU - Che-Mai Chang
AU - Wan-Chen Huang
AU - Wei-Chiao Chang
AU - Neil Herring
AU - Annika Winbo
AU - Guoliang Hao
AU - Jie Zhang
AU - Dan Li
PY - 2026
DA - 2026/07/30
JO - Cardiovascular Diabetology
DO - 10.1186/s12933-026-03288-9
UR - https://doi.org/10.1186/s12933-026-03288-9
AB - Background: Diabetic cardiomyopathy (DCM) represents a distinct form of heart failure occurring independently of coronary artery disease, yet effective treatments remain limited. While cAMP signaling alterations have been reported in diabetic hearts, the compartment-specific consequences across distinct subcellular pools remain poorly understood. We investigated cytosolic and mitochondrial cAMP microdomain dysfunction in DCM, focusing on ADCY2 and PDE4DIP as potential regulators, and evaluated fibroblast growth factor 1 (FGF1) as a therapeutic intervention using integrated two-dimensional (2D) and three-dimensional (3D) human induced pluripotent stem cell (hiPSC)-derived cardiac models. Methods: Healthy hiPSC-derived cardiomyocytes were exposed to a diabetic-like environment (high glucose, endothelin-1 and cortisol) in 2D and 3D culture. Two-dimensional studies included bulk RNA sequencing, FRET-based cAMP measurements in cytosolic and mitochondrial outer membrane compartments, and microelectrode array electrophysiology. Three-dimensional cardiac microtissues were assessed by optical mapping to characterize spatial calcium dynamics and conduction properties. Results: DCM exhibited compartment-specific cAMP dysregulation associated with ADCY2 downregulation and PDE4DIP upregulation. Cytosolic compartments showed preserved baseline cAMP but attenuated forskolin responsiveness, while the mitochondrial outer membrane displayed both reduced baseline cAMP and impaired stimulated responses. Transcriptomic analysis revealed transcriptional signatures consistent with metabolic remodeling, including upregulated fatty acid oxidation machinery, Complex I dysfunction, and elevated phospholamban and CASQ2 expression. 3D optical mapping demonstrated reduced calcium transient amplitude, prolonged transient duration, and severely impaired calcium propagation velocity. FGF1 treatment normalized PDE4DIP expression and restored cAMP dynamics in 2D cultures and partially improved calcium transient amplitude in 3D microtissues, though conduction defects persisted. Conclusions: Compartment-specific impairment of cAMP microdomains is associated with DCM pathogenesis. Integrated 2D–3D assessment reveals that FGF1 improves cAMP signaling but does not fully reverse metabolic, electrophysiological, or structural abnormalities, highlighting the need for combination therapies targeting both cAMP pathway integrity and conduction restoration. Graphical abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12933-026-03288-9.
SN - 1475-2840
ER -