Hippo signaling-linked circulating microRNA networks are associated with cardiovascular disease in type 2 diabetes

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.