Abstract
The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.
Highlights
The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart
We further investigated the distribution of these miRNAs in cardiomyocytes and non-cardiomyocytes and found that miR-19a is enriched in cardiomyocytes of adult mouse hearts (Fig. 1b)
Systemic delivery of miR-19a/miR-19b mimics in post myocardial infarction (MI) mice produces clear cardiac protection. Given their role in cardiac protection in mouse hearts and the fact that these miRNAs are highly conserved between mice and humans, miR-19a and miR-19b may be uniquely suited to become therapeutic targets for cardiac regeneration and heart failure
Summary
The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. The function of miRNAs in regulating cardiomyocyte proliferation and heart regeneration was linked to the Hippo/Yap pathway, in which members of the miR302-367 cluster directly target key components of the Hippo/Yap pathway. A recent study showed that a single-dose intracardiac injection of miR-199a-3p and miR-590-3p mimics was able to protect cardiac function in response to MI, underscoring the therapeutic potential of miRNAs in cardiomyopathy[12]. Using mouse models of genetic mutation and overexpression, we have previously reported that the miR-17-92 cluster plays a critical role in cardiomyocyte proliferation in embryonic, postnatal, and adult hearts. We report that intra-cardiac injection or systemic delivery of miR19a/19b mimics or using an adeno-associated virus 9 (AAV9) delivery method to overexpress miR-19a/19b in mouse heart reduces MI-induced cardiac injury and preserved cardiac function. Our results suggest that miR-19a/19b could become therapeutic targets to prevent and treat cardiac disease
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