{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusions: 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.\n\nGraphical abstract:\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12933-026-03288-9.",
  "abstract_shown": true,
  "affiliations": [
    "Burdon Sanderson Cardiac Science Centre and BHF Centre of Research Excellence, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK",
    "Institute of Electrophysiology, Henan Academy of Innovations in Medical Science, Zhengzhou, 450000 China",
    "Ningbo No.2 Hospital, Wenzhou Medical University, No.41, Xibei Street, Ningbo, Zhejiang China",
    "Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan",
    "Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193 China",
    "Ellison Institute of Technology, Winchester House, Heatley Road, The Oxford Science Park, Littlemore, Oxford UK",
    "Single-Molecule Biology Core Lab, Institute of Cellular and Organismic Biology (ICOB), Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 115 Taiwan",
    "Department of Public Health and Clinical Medicine, Faculty of Medicine, Umeå University, Umeå, Sweden",
    "CAMS Oxford Institute, Peking Union Medical College, Chinese Academy of Medical Sciences, University of Oxford, Oxford, UK"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kun Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Kazuki Osuka"
    },
    {
      "affs": [
        1
      ],
      "name": "Mengying Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Rhea Takhar"
    },
    {
      "affs": [
        0
      ],
      "name": "Neda Mohammadi"
    },
    {
      "affs": [
        0
      ],
      "name": "Adam Trevett"
    },
    {
      "affs": [
        2
      ],
      "name": "Jinyan Zhong"
    },
    {
      "affs": [
        3
      ],
      "name": "Ching-Wen Chang"
    },
    {
      "affs": [
        2
      ],
      "name": "Nan Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xinyu Hu"
    },
    {
      "affs": [
        1
      ],
      "name": "Ruirui Dong"
    },
    {
      "affs": [
        4
      ],
      "name": "Shunan Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "YoonYoung Choi"
    },
    {
      "affs": [
        0
      ],
      "name": "Thamali Ayagama"
    },
    {
      "affs": [
        5
      ],
      "name": "Mingyu Li"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Linna Zhou"
    },
    {
      "affs": [
        3
      ],
      "name": "Che-Mai Chang"
    },
    {
      "affs": [
        6
      ],
      "name": "Wan-Chen Huang"
    },
    {
      "affs": [
        3
      ],
      "name": "Wei-Chiao Chang"
    },
    {
      "affs": [
        0
      ],
      "name": "Neil Herring"
    },
    {
      "affs": [
        7
      ],
      "name": "Annika Winbo"
    },
    {
      "affs": [
        1
      ],
      "name": "Guoliang Hao"
    },
    {
      "affs": [
        2
      ],
      "name": "Jie Zhang"
    },
    {
      "affs": [
        0,
        8
      ],
      "name": "Dan Li",
      "orcid": "0000-0003-2230-9300"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/02j8bxwdaw1v5.bib",
  "cited_by": 0,
  "doi": "10.1186/s12933-026-03288-9",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712054/",
  "id": "02j8bxwdaw1v5",
  "issns": [
    "1475-2840"
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  "landing_url": "https://doi.org/10.1186/s12933-026-03288-9",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
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      "openalex",
      "1312|Phosphodiesterase function and regulation"
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  "openalex": "W7171794300",
  "pdf_url": null,
  "pmcid": "PMC13712054",
  "pmid": "42934709",
  "published": "2026-07-30",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/02j8bxwdaw1v5.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:22:43Z",
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Phosphodiesterase function and regulation",
      "subfield": "molecular-biology"
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  ],
  "title": "Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1",
  "title_text": "Compartment-specific cAMP dysfunction in diabetic cardiomyopathy in hiPSC-derived cardiomyocytes: therapeutic potential of fibroblast growth factor 1",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:43Z",
  "url": "https://research.draconitic.com/paper/02j8bxwdaw1v5",
  "venue": "Cardiovascular Diabetology",
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}