Key result
MiR-519 delivery post-MI boosts cardiomyocyte proliferation, cuts scar size, and reduces mortality in mice.
Why the study?
The adult human heart has limited regenerative capacity after MI, requiring strategies that coordinate cardiomyocyte proliferation and angiogenesis without fibrosis. After miR-519 emerged as a potent activator of cardiomyocyte cell-cycle activity, its regenerative potential, mechanisms, and in vivo therapeutic efficacy after MI needed characterization.
Does miR-519 delivery promote cardiomyocyte proliferation, angiogenesis, and cardiac repair in human cellular models and adult mice following myocardial infarction?
Does miR-519 delivery promote cardiomyocyte proliferation, angiogenesis, and cardiac repair in human cellular models and adult mice following myocardial infarction?
MiR-519 promotes post-MI cardiac repair in preclinical models by directly repressing cell-cycle inhibitors p21 and p57 to drive cardiomyocyte proliferation and angiogenesis while reducing scar size and mortality.
Background Myocardial infarction (MI) causes irreversible cardiomyocyte (CM) loss, adverse ventricular remodeling, and heart failure due to the limited regenerative capacity of the adult human heart. Effective cardiac repair requires the coordinated induction of CM proliferation and angiogenesis without promoting fibrosis. Following an unbiased high-throughput functional screen of 2,019 microRNAs (miRs) in human induced pluripotent stem cell-derived CMs (hiPSC-CMs), miR-519e-3p (miR-519) emerged as a potent activator of CM cell-cycle activity. Purpose To characterize the regenerative potential and underlying mechanisms of miR-519 in human multicellular systems and evaluate its therapeutic efficacy after MI in vivo. Methods MiR-519-mimics or miR-scrambled (control) were transfected into hiPSC-CMs, human aortic endothelial cells (HAECs), and human cardiac fibroblasts (cFBs). CM proliferation was assessed via immunofluorescence (IF) for 5-ethynyl-2′-deoxyuridine (EdU), phospho-Histone H3 (H3P), and Aurora B kinase (Au-B). Cell-cycle regulators were analyzed via Western blot (WB) and quantitative PCR (qPCR). Anti-apoptotic effects were evaluated following doxorubicin (Dox) exposure. Angiogenesis and fibrosis were assessed via tube formation and α-smooth muscle actin (α-SMA) IF staining. MI was induced in adult mice followed by intramyocardial miRNA delivery. Proliferative response was assessed by IF and molecular methods. Direct targets were identified via Argonaute-2 immunoprecipitation (Ago2-IP) following RNA-sequencing. Results MiR-519 significantly increased EdU-incorporation in hiPSC-CM and H3P- and Au-B-positive hiPSC-CM (p<0.01, n=10), with higher expression of Cyclin A2 and suppression of p21 (p<0.01, n=4), indicating progression from cell-cycle re-entry through cytokinesis. Viability was preserved in miR-519-treated hiPSC-CMs after doxorubicin exposure (p<0.05, n=6). In addition, miR-519 enhanced angiogenic activity, increasing mesh formation (p<0.001, n=6) and tube length (p<0.05, n=6) but had no effect on proliferation and α-SMA expression in cFBs (p=ns, n=8). In vivo, miR-519 delivery after MI increased CM proliferation in the infarct border zone, as assessed through H3P and Au-B-staining, suppressed p21 expression (p<0.05, n=5), and decreased fibrotic scar size (p<0.01, n=5), resulting in lower rates of death (p<0.05, n=12). Ago2-IP RNA-sequencing identified key cell cycle inhibitors p21 and p57 as direct targets of miR-519. Conclusion This study suggests that MiR-519 promotes cardiac repair through induction of CM proliferation, preserved cell survival and enhanced angiogenic capacity, thereby improving outcomes after myocardial infarction. These findings identify miR-519 as a promising therapeutic candidate for cardiac injury.
No takes yet. Share an insight, caveat, or question.
Gong et al. (2026) studied Myocardial infarction. miR-519e-3p (miR-519) mimics / intramyocardial delivery vs. miR-scrambled (control) was evaluated on Cardiomyocyte proliferation, fibrotic scar size, and mortality post-MI (p=<0.05). MiR-519 delivery post-MI increased cardiomyocyte proliferation, reduced fibrotic scar size (p<0.01, n=5), and lowered mortality rates (p<0.05, n=12) in mice.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: