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| Item Type: | Article |
|---|---|
| Title: | Hippo signaling-linked circulating microRNA networks are associated with cardiovascular disease in type 2 diabetes |
| Creators: |
Besharat, Zein Mersini  ORCID: https://orcid.org/0000-0003-0317-9854, Trocchianesi, Sofia ORCID: https://orcid.org/0000-0002-8157-2638, Grieco, Giuseppina Emanuela ORCID: https://orcid.org/0000-0001-7325-6128, Autilio, Tanja Milena ORCID: https://orcid.org/0000-0003-4092-1990, Alfano, Caterina ORCID: https://orcid.org/0000-0002-7296-8112, Dardano, Angela, Fignani, Daniela ORCID: https://orcid.org/0000-0001-8803-5846, Splendiani, Elena ORCID: https://orcid.org/0000-0003-4259-9093, Citarella, Anna ORCID: https://orcid.org/0000-0003-1290-4990, Sabato, Claudia ORCID: https://orcid.org/0000-0001-7533-4660, Spinello, Zaira ORCID: https://orcid.org/0000-0002-7016-6538, Catanzaro, Giuseppina ORCID: https://orcid.org/0000-0001-8427-9691, Po, Agnese ORCID: https://orcid.org/0000-0002-9346-8782, Petti, Manuela ORCID: https://orcid.org/0000-0002-0149-161X, Farina, Lorenzo ORCID: https://orcid.org/0000-0001-8314-6029, Venneri, Mary Anna ORCID: https://orcid.org/0000-0002-0687-8135, Lauro, Davide ORCID: https://orcid.org/0000-0002-8597-4415, Fadini, Gian Paolo ORCID: https://orcid.org/0000-0002-6510-2097, Dotta, Francesco ORCID: https://orcid.org/0000-0003-4947-7478, Sebastiani, Guido ORCID: https://orcid.org/0000-0003-4374-8564, Natali, Andrea ORCID: https://orcid.org/0000-0002-8465-7717 and Ferretti, Elisabetta ORCID: https://orcid.org/0000-0001-7265-6429
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| Abstract: | CONTEXT: Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease (CVD). Circulating microRNAs (miRNAs) are promising biomarkers for patient stratification and may provide mechanistic insight into dysregulated pathways in T2D-associated CVD. OBJECTIVE: This work aimed to identify circulating miRNA signatures in T2D patients with CVD (T2D-CVD) vs T2D patients without CVD using a novel network-based medicine approach. METHODS: Patients (n = 110) were stratified into T2D and T2D-CVD groups based on the absence or presence of macrovascular complications. Circulating miRNAs, proinflammatory cytokines, and growth factors were profiled in a discovery cohort (n = 80) and confirmed in a validation cohort (n = 30). Differential expression, network-based approaches, and pathway enrichment analyses identified miRNA signatures, coexpression communities, hub miRNAs, and associated signaling pathways. RESULTS: T2D-CVD patients showed a set of elevated inflammatory cytokines and circulating miRNAs. Particularly, 19 miRNAs were differentially expressed between T2D-CVD and T2D patients. Pathway enrichment of these miRNAs highlighted Hippo signaling together with transforming growth factor-β, mechanistic target of rapamycin, Wnt, and PI3K-Akt pathways. Network analysis identified a coexpression community of 34 miRNAs, including hub miRNAs let-7a-5p, miR-132-3p, and miR-1306-3p, all linked to Hippo signaling. Key miRNA interactions were validated, and differentially expressed and hub miRNAs both correlated with inflammatory mediators such as PAR-1, CXCL1, and NEMO, which are linked to Hippo pathway regulation. CONCLUSION: This study identified a network of circulating miRNAs associated with inflammatory cytokines and Hippo signaling pathway in T2D-CVD. These findings reveal novel molecular aspects of the systemic inflammation characterizing T2D-CVD and support the potential of Hippo-related circulating miRNAs as mechanistic biomarkers for cardiovascular risk in T2D. |
| Keywords: | Circulating miRNA, Type 2 Diabetes, Cardiovascular Disease, Coexpression Network, Hippo Signaling Pathway |
| Source: | Journal of the Endocrine Society |
| ISSN: | 2472-1972 |
| Publisher: | Oxford University Press |
| Volume: | 10 |
| Number: | 11 |
| Page Range: | bvag229 |
| Date: | November 2026 |
| Official Publication: | https://doi.org/10.1210/jendso/bvag229 |
| PubMed: | View item in PubMed |
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