Embracing Bias

Abstract

Cardiovascular disease remains the leading cause of mortality and morbidity in the developed world, despite recent advances in therapeutic interventions, with an estimated annual cost in the United States alone of >$312 billion.1 This emphasizes the demand for a greater understanding of the molecular mechanisms involved in cardiovascular pathophysiology and demonstrates the desperate need for innovative strategies for both treatment and prevention.2 Article, see p 833 Recent reports suggest an emerging role for microRNAs (miRs), small noncoding nucleic acid regulators of mRNA, in the development and progression of cardiovascular disease. miRs, a large family of highly conserved RNAs 18-25 nucleotides in length, are essential in the post-transcriptional regulation of gene expression. Typically, miRs are encoded within the introns of protein-coding genes; they also exist intergenically under the control of their own promoters.2,3 Transcription of these regions by RNA polymerase II generates miR precursors known as primary-miRs (pri-miRs), which are converted to mature miRs through the activities of 2 members of the RNase III family of enzymes. Cleavage of pri-miR by the enzyme Drosha forms a ≈70 nucleotide sequence, termed pre-miR, that is subsequently exported to the cytoplasm. Final processing by Dicer creates the ≈20 nucleotide mature miR that incorporates into the miR-induced silencing complex, forming the active enzyme capable of inducing mRNA translational repression or degradation.2,4 Hundreds of distinct mRNAs can be influenced by an individual miR, allowing a single miR or family of miRs to coordinate substantial alterations in physiology and function collectively. It is increasingly clear that appropriate miR expression is crucial in cardiac development, function, and disease. Numerous cardiac complications, including myocardial infarction, hypertrophy, and remodeling, can be exacerbated by improper miR regulation.2,3 Intriguingly, pharmacological modulation of several miRs has been shown to reduce cardiac pathophysiology …