Am J Physiol Heart Circ Physiol. 2025 Dec 10. doi: 10.1152/ajpheart.00364.2025. Online ahead of print.
ABSTRACT
MicroRNAs (miRNAs), short non-coding RNAs that post-transcriptionally regulate gene expression, have emerged as critical regulators of cardiac genes. Although circulating miRNAs have been implicated in cardiovascular disease, their precise functional roles remain poorly understood. Using Drosophila as a model, we applied miRNA sponge technology to competitively inhibit miR-6 (the mammalian homolog, miR-27), enabling us to systematically assess its impact on heart function, morphology, and lifespan. Functional and structural cardiac changes were analyzed with SOHA (semi-automatic optical heartbeat analysis) software and immunohistochemistry. In silico target analysis revealed 149 conserved predicted gene targets shared by this miRNA family, highlighting its potential regulatory scope. Our findings uncover a novel cardioprotective role for miR-6 inhibition, demonstrating that heart-specific miR-6 suppression mitigates age-related changes to heart size and function, significantly extends lifespan, and leads to increased lipid accumulation in cardiomyocytes. Importantly, we observed elevated expression of the conserved target gene low-density lipoprotein receptor related protein 1 (LRP1) in miR-6-inhibited hearts and genetic disruption of LRP1 expression in miR-6 inhibition decreased lipid accumulation in the heart. Conservation of miR-27b and LRP1B expression in mammalian cardiac tissue further validates the translational relevance of these findings.
PMID:41369686 | DOI:10.1152/ajpheart.00364.2025