Identification and Characterization of MicroRNAs Modulating Cardiac Hypertrophy

Braga, Luca (2017). Identification and Characterization of MicroRNAs Modulating Cardiac Hypertrophy. PhD thesis The Open University.



The adult heart is capable of remodelling in response to different pathological stimuli; in most cases, a phase of compensated hypertrophy evolves into frank dysfunction and heart failure. To identify microRNAs able to prevent cardiac hypertrophy and preserve cardiac function, we performed a high-content microscopy, high-throughput functional screening for human microRNAs able to reduce neonatal cardiomyocyte (CM) cell size using a whole-genome microRNA library. The most effective anti-hypertrophic microRNA was hsa-miR-665. In a model of transverse abdominal aortic constriction (TAC) in 8 weeks old CD1 mice (n=14 per group), AAV9-mediated delivery of miR-665 showed remarkable capacity to protect against pathological cardiac hypertrophy and preserve function over time. This effect was observed when the vectors were delivered either before (LVEF at 60 day after TAC: 51.3% ±5.8% in treated vs 34.82% ±0.77% in controls; P<0.005) or after hypertrophy onset (LVEF at 60 days after TAC: 57.5%±5.60% in treated vs 28.4%±15% in controls; P<0.001). Global mRNA changes in hearts treated with miR-665 were evaluated by mRNA deep sequencing. All the 43 genes, for which siRNA were available, out of the 67 genes that were found to be significantly expressed ≤2 fold over control were individually down-regulated by specific siRNAs and tested for being direct miR-665 targets. This approach identified three sarcomeric proteins as direct mediators of miR-665 activity, namely Enah, Fhl1 and Xirp2, which are known to be involved in sarcomeric mechanotransduction and myofibrillar remodelling. In conclusion, miR-665 represents an important tool to decipher the molecular mechanisms of hypertrophy and offers a potential lead for the development of new biotherapeutics.

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