MiR-25 in heart failure.

Abstract

Recent work by Wahlquist et al 1 showed miR-25 to reduce levels of rco/endoplasmic reticulum calcium-ATPase (SERCA) 2a during heart failure, whereas therapeutic inhibition of this microRNA (miRNA) was able to reverse pre-established heart failure in a mouse model of pressure overload. Although these data suggest that miR-25 might be a drug target for the treatment of heart failure, further in vivo analysis is required before we can consider miR-25 inhibition for clinical application. Recently, Wahlquist et al1 reported on the pathological upregulation of miR-25 during heart failure and showed that inhibition was able to block and reverse the disease in mice. Although an increase in cardiac miR-25 levels caused a decline in cardiac function, anti–miR-based inhibition of miR-25 halted established heart failure at least in part by increasing the mRNA of SERCA2a. This is intriguing because phase II clinical data from the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial has demonstrated that gene therapy to increase SERCA2a levels in humans delays the progression of chronic heart failure. This could imply that pharmacological regulation of miR-25 may regulate at least 1 clinically validated target, which may be more straightforward than current gene therapy approaches. However, miRNA biology seems to sketch a somewhat more complex picture than a miRNA functioning through 1 single-gene target. In addition, conflicting data on the cardiac functions of miR-25 highlight the need for further investigation before advancing miR-25 as a clinical target for heart failure. miRNAs are short single-stranded noncoding RNAs that modulate the expression of target proteins by annealing to complementary sequences in their target mRNAs.2 It is thought that a single vertebrate miRNA on average targets a few hundred transcripts.3,4 Because individual miRNAs often target numerous related mRNAs that encode multiple components of …