MicroRNAs Add a New Dimension to Cardiovascular Disease

Abstract

Cardiovascular disease is the predominant cause of human morbidity and mortality in developed countries. Thus, extraordinary effort has been devoted to determining the molecular and pathophysiological characteristics of the diseased heart and vasculature with the goal of developing novel diagnostic and therapeutic strategies to combat cardiovascular disease. The collective work of multiple research groups has uncovered a complex transcriptional and posttranscriptional regulatory circuit, the integrity of which is essential for the maintenance of cardiac homeostasis. Mutations in or aberrant expression of various transcriptional and posttranscriptional regulators have now been correlated with human cardiac disease, and pharmacological modulation of the activity of these target genes is a major focus of ongoing research. Recently, a novel class of small noncoding RNAs, called microRNAs (miRNAs), was identified as important transcriptional and posttranscriptional inhibitors of gene expression thought to “fine tune” the translational output of target messenger RNAs (mRNAs).1,2 miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become an intriguing target for therapeutic intervention. This review focuses on the basic biology and mechanism of action of miRNAs specifically pertaining to cardiovascular disorders and addresses the potential for miRNAs to be targeted therapeutically in the treatment of cardiovascular disease. miRNAs originate from longer precursor RNAs called primary miRNAs that are regulated by conventional transcription factors and transcribed by RNA polymerase II. Primary miRNAs are hundreds to thousands of nucleotides long and are processed in the nucleus into an ≈70- to 100-nucleotide hairpin-shaped precursor miRNA by the RNase III enzyme Drosha and the double-stranded RNA binding protein DGCR8. The precursor miRNA is then transported into the cytoplasm by the nuclear export factor exportin 5 and further processed into an ≈19- to 25-nucleotide double-stranded RNA by the RNaseIII enzyme Dicer. This duplex miRNA is then incorporated into the RNA-induced silencing complex. One …