MicroRNAs as a therapeutic target for cardiovascular diseases

Abstract

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.

1

Biogenesis of miRNA and its regulatory mechanisms: miRNAs are encoded from either intergenic regions or introns and sometimes more than one encoded miRNA shares the same transcript (polycistronic). The primary miRNA (pri-miRNA), an approximately 200 kilobases long, capped and polyadenylated transcript, is transcribed by RNA polymerase III (or II) from any of the above mentioned encoding regions of miRNA. The pri-miRNA from intergenic and intronic regions is shown in the upper panel and from polycistronic region is shown in the lower panel of pri-miRNA. Drosha (an RNase III enzyme) along with Pasha (a double strand RNA binding protein) processes pri-miRNA into approximately 70 nucleotide pre-miRNA by cleaving the 5′ cap and polyadenylated tail. The pre-miRNA is transported from the nucleus to the cytoplasm by RAN-GTP exportin 5. Dicer (another RNase III endonuclease) cleaves pre-miRNA into double stranded transient duplex miRNA (22 nucleotides). The double stranded miRNA dissociates into single strands, and only one strand is retained as mature miRNA and it binds to RNA induced silencing complex (RISC). The miRNA-RISC complex regulates the dose of a particular protein by either degrading the complimentary mRNA by using RNAi mechanism or by inhibiting the translational machinery of protein.

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Putative therapy of cardiovascular diseases through microRNomics: in cardiovascular diseases Dicer and several miRNAs are dysregulated in heart and shows differential expressions. The pathological condition can be ameliorated by either knocking down those miRNAs, which are up-regulated or enhancing those, which are down-regulated. Another strategy can be the use of stem cells to replenish the diseased cells by new cells. The miRNAs in stem cells can be used to direct them for differentiation to produce specific type of cells required for mitigating the pathology.