Therapeutic microRNA-based strategies in heart failure

Background:MicroRNAs (miRNAs) have been studied intensively since their discovery more than two decades ago, which led to a drastic change in our understanding of regulatory epigenetic processes. MicroRNAs (22 nucleotides in length) are involved in several cell processes by repressing messenger RNA (mRNA) translation mainly via binding at the complementary 3′-untranslated region, thus modulating gene expression at the post-transcriptional level. In cardiac development, miRNAs are needed for the formation of normal, functional heart tissue and a variety of miRNAs have been discovered as important regulators of several phases in cardiac development.The importance of miRNAs was originally demonstrated in embryonic development by modifications in Dicer, an enzyme involved in miRNA processing. Dicer1 gene targeting in mice resulted in early embryonic death. Furthermore, cardiac-specific deletion of Dicer shortly after embryonic heart formation resulted in cardiac malformations, heart failure and eventually death .Deletion of Dicer in the postnatal myocardium induced cardiac remodelling, increased atrial size, and resulted in early lethality. These results led to an increasing number of studies identifying specific miRNAs associated with several phases of cardiac development.MicroRNAs (miRNAs) with key roles in cardiac fibrosis and hypertrophy in response to cardiac injury or overload. MiR-1, miR-21, miR-29, and miR-133 are presented with their known targets. The expression of miR-1, miR-29, and miR-133 is downregulated in cardiac tissue in response to cardiac injury or overload, leading to a decreased negative regulation of their mRNA targets. MiR-21 is upregulated in response to cardiac injury or overload, resulting in increased negative regulation of the corresponding targets. Moreover, long-term follow-up studies are necessary to identify any side-effects that may develop after months or years. Furthermore, circulating miRNAs are promising new biomarkers in heart failure for diagnostic and prognostic purposes, and to identify a patient’s response to therapy. Several miRNAs have been related to important mechanisms leading to heart failure, such as hypertrophy and fibrosis. An increasing number of miRNAs and miRNA targets have been reported in heart failure models, increasing our insight into the pathophysiology of this syndrome.Conclusions:Loss- and gain-of-function experiments revealed an important role for miRNA mimics and antimirs—an interesting development that might broaden the treatment options for patients with heart failure. Together, miRNAs and miRNA-based therapies comprise one of the most innovative advancements of the last years and hold great promise for future clinical application in heart failure.

Keywords:

microRNA , heart failure , miRNA-based therapies