MicroRNAs--regulators of signaling networks in dilated cardiomyopathy

Abstract

MicroRNAs (miRNAs) are endogenous small non-coding ribonucleotides that regulate expression of target genes governing diverse biological functions. Mechanistically, miRNA binding to the target complimentary sequences on the mRNA results in degradation or inhibition of protein translation. The short guiding and binding sequence of miRNA allows them to target a large repertoire of transcripts altering expression of many proteins. These miRNA targets are not restricted to specific signaling pathways but to a diverse group of transcripts, which harbor the target complimentary sequence. miRNA targeting of these diverse transcripts result in regulation of multiple signaling pathways establishing miRNAs as regulators of systems biomolecular networks. Accumulating evidence shows that miRNAs play an important role in cardiac development, hypertrophy, and failure, thereby are integral to regulating adaptive and maladaptive remodeling. Since cardiac remodeling and failure is a complex phenotype, it is apparent that global biomolecular networks and miRNAs profiles would be altered. Indeed, the miRNA profiles are varied with different etiologies of heart failure indicating that miRNAs could be the global regulators. Although the idea of miRNA being global regulators is not new, we believe that the time is ripe to discuss the role of miRNAs in regulating biomolecular networks. We discuss in the review, the use of Ingenuity Pathways Analysis algorithms with predicted targets of altered miRNA in dilated cardiomyopathy to computationally determine the alterations in canonical functional pathways and to generate biomolecular networks.

Fig. 1

Heat map of significantly altered miRNAs (miRNome) of individual patient samples from non-failing and failing human hearts diagnosed with dilated cardiomyopathy (DCM) [29]

Fig. 2

Systems perspective of complex disease pathology encompassing integrated analysis at each level. The scheme represents a multilayered regulation that has been effectively studied to provide a global analysis at each layer. Contribution by miRNA “miRNome” has been added to the multilayered regulation to give another layer of regulation in complex global signaling network

Fig. 3

A representative network showing NF-κB as the hub or high connectivity node. The hub is the center of the web of signaling connections and NF-κB is connected to nearly all the molecules in the network. Altered miRNAs in end-stage heart failure are overlaid with their respective predicted targets. miRNA represented in green are downregulated and in red are upregulated in end-stage human dilated cardiomyopathy. Importantly, NF-κB is not a predicted target to any of the altered miRNAs “miRNome” in DCM, yet it could be regulated by alterations in miRNA targets [29]