Why a microRNA’s absence makes the heart grow larger

Drawnel et al. describe how a calcium channel and a microRNA regulate each other to promote pathological remodeling of heart muscle.

In response to stresses such as infarction, aging, or hypertension, cardiac muscle cells grow to provide the heart with extra capacity, but this hypertrophy often results in cell death and heart failure. The inositol triphosphate receptor II (IP₃RII) calcium channel is up-regulated in hypertrophic cardiac muscle. The calcium it releases from sarcoplasmic and perinuclear stores provokes cardiac arrhythmias and induces changes in gene transcription that promote cardiomyocyte growth and remodeling. How IP₃RII levels are regulated is unknown, however.

Drawnel et al. found that IP₃RII’s expression was normally restricted by miR-133a, a microRNA whose levels decrease during hypertrophy to permit cardiac remodeling. Blocking the interaction between miR-133a and IP₃RII mRNA increased the channel’s expression and induced hypertrophy in cardiomyocytes. The researchers then investigated what triggers miR-133a’s down-regulation during hypertrophy and found that the calcium released through IP₃RII itself was required to switch off miR-133a transcription. Blocking IP₃-induced calcium release prevented miR-133a’s repression in response to hypertrophic stimuli, thereby inhibiting IP₃RII up-regulation.

IP₃RII therefore initiates a positive feedback loop to promote its own expression and drive cardiac hypertrophy. The authors now want to investigate how calcium signaling represses miR-133a; their initial results suggest that calcium release converts the transcription factor SRF into an inhibitor of miR-133a expression.