MicroRNA Therapeutics in Cardiovascular Disease

Abstract

MicroRNAs are endogenous single-stranded RNAs of approximately 22 nucleotides in length which decrease the level of expression of specifi c proteins. miRNAs are involved in many pathologic conditions such as cancers and neuropsychiatric and metabolic diseases. In cardiovascular diseases, miRNAs have been shown to be involved in the proliferation of cardiomyocytes and non-myocyte cardiac cells, in cardiac hypertrophy and apoptosis, in the occurrence of atrial and ventricular arrhythmias, in vascular angiogenesis and smooth muscle cell pathologies, and in atherosclerosis. In heart failure, miRNAs have been shown to promote or inhibit hypertrophy and remodeling as well as to modulate cardiac pump function. By considering a few specifi c examples illustrating the value and complexity of targeting miRNAs, this chapter will describe the key data demonstrating the potential of miRNAs either to prevent cardiac hypertrophy (miR-208) or to improve cardiac function (miR-25) in heart failure. In the biogenesis of miRNAs, a passenger strand miRNA, called miRNA*, is usually degraded. The effects of miR-21* illustrate a situation where miRNA* exhibits a biological activity. Finally, miRNAbased therapeutics is nearly reaching human trials in the cardiovascular disease area. However, several questions remain to be fully investigated to progress such therapeutic approaches successfully. These include strategies to improve druggability parameters and delivery characteristics of selected candidates as well as approaches required to demonstrate clearly the effi cacy/safety ratio of such novel therapies.