Circulating exosomal miR-550a-5p/miR-665 identify coronary microvascular dysfunction and drive endothelial-myocyte...

This study aimed to identify circulating exosomal microRNAs for early detection of coronary microvascular dysfunction (MD) and stratification of myocardial injury risk in type 2 diabetes, and to test whether miR-550a-5p derived from endothelial cell models mechanistically links endothelial stress to cardiomyocyte vulnerability via Hippo-eNOS signaling and vesicular transfer.

We combined Gene Expression Omnibus (GEO)-guided discovery and compendium prioritization with clinical and mechanistic validation. Plasma exosomal miR-550a-5p/miR-665 were quantified in a well-phenotyped Type 2 Diabetes Mellitus (T2DM) cohort and related to MD and myocardial injury. In vitro, miR-550a-5p was modulated in human cardiac microvascular endothelial cells under high glucose to profile Hippo-YAP/eNOS signaling, and its exosomal transfer effects on human cardiomyocytes were evaluated, with Hippo inhibition applied as a rescue strategy.

Exosomal miR-550a-5p and miR-665 were elevated in MD and further increased with myocardial injury, showing useful diagnostic performance and independent associations. miR-550a-5p inhibition restored endothelial viability, migration, tube formation and p-eNOS/eNOS, reduced MST1/LATS1 activation, and increased Yes-associated protein (YAP) activity. Endothelial exosomes delivered miR-550a-5p to cardiomyocytes, aggravating apoptosis and oxidative stress; donor-cell miR-550a-5p suppression and Hippo inhibition mitigated these effects.

Exosomal miR-550a-5p, together with miR-665, functions as a dual-utility signal, serving as an accessible biomarker for coronary MD and as a mechanistic mediator in endothelial-to-cardiomyocyte exosomal signaling. These findings support earlier detection, risk stratification, and mechanism-guided intervention in T2DM. Future priorities include external validation, longitudinal kinetic assessment, and target-network mapping.