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Cardiac Fibrosis in Dilated Cardiomyopathy: Transcriptomics Insights, Histological Correlations, and Organoid Model Verifications [RNA-seq II]

ABSTRACT: Dilated cardiomyopathy (DCM) represents a leading cause of heart failure among younger adults. Despite endomyocardial biopsy (EMB) transcriptome enriching our understanding of DCM, the link between its gene expression and phenotype remains unclear. RNA-seq analysis of 58 DCM samples and 12 publicly available control samples unveiled about 25,000 transcripts. A principal component analysis highlighted a distinct DCM-control separation. WGCNA revealed four transcriptome modules strongly associated with DCM. The purple module, which is the DCM-related module, was enriched with fibrosis-related genes and showed FSTL3 as a pivotal DCM-associated gene. , We further validated using cardiac fibrosis organoid models. Concurrently, FSTL3 expression reflected cardiac organoid fibrosis intensity. Furthermore, FGFR1 expression, along with its phosphorylation in DCM myocardial tissue, was correlated with fibrosis severity. Cardiac fibrosis organoid models treated with AZD4547, a selective FGFR1 inhibitor, suppressed fibrosis-related markers, underscoring its potential therapeutic efficacy against DCM-related cardiac fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246298 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:Background: Galectin-3 is upregulated in heart disease, and its inhibition has been reported to confer benefits on cardiac remodeling and dysfunction. It remains unknown whether galectin-3 plays a biological role in a setting of dilated cardiomyopathy (DCM). We determined galectin-3 expression in transgenic (TG) mice with cardiac-restricted overexpression of mammalian sterile 20-like kinase 1 (Mst1-TG), and studied the effects of pharmacological and genetic inhibition of galectin-3 on the DCM phenotype. Methods and results: The DCM phenotype of male Mst1-TG mice was assessed at 2, 3 and 6 months of age. Galectin-3 deletion in Mst1-TG mice was achieved by cross-breeding Mst1-TG with galectin-3 knockout (KO) mice to produce genotypes of non-TG (nTG), KO, Mst1-TG, and Mst1-TG mice with partial or complete deletion of the galectin-3 gene. Pharmacological inhibition of galectin-3 was tested by treating Mst1-TG mice with modified citrus pectin for 4 months. Changes in the DCM phenotype were assessed by serial echocardiography, ECG recording and biochemical assays. Mst1-TG mice exhibited upregulated levels of cardiac galectin-3 expression by 40~50-fold, atrial dilatation, reduced left ventricular (LV) ejection fraction, increased LV volume at systole and diastole, atrial conduction delay, severe cardiac fibrosis, and upregulated fibrosis-related genes. Galectin-3 gene deletion in Mst1-TG mice attenuates increased LV volume at systole and diastole, atrial conduction delay and cardiac fibrogenesis. Treatment with modified citrus pectin in Mst1-TG mice did not confer benefit on the DCM phenotype, possibly due to the very high expression of galectin-3. Conclusion: Galectin-3 expression is markedly increased in Mst1-TG hearts exhibiting DCM. Galectin-3 gene deletion effectively suppressed cardiac fibrotic signaling and LV dilatation, and was associated with better function. Thus, suppression of galectin-3 expression may represent a potential therapeutic approach in DCM. The development of new galectin-3 inhibitors are warranted.

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Cardiac Fibrosis in Dilated Cardiomyopathy: Transcriptomics Insights, Histological Correlations, and Organoid Model Verifications [RNA-seq II]

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