IGF2BP2 is Induced by Stress in the Heart and Mediates Dilated Cardiomyopathy

Abstract

The IGF2BP family of RNA binding proteins consists of three paralogs that regulate intracellular RNA localization, RNA stability, and translational control. Although IGF2BP1 and 3 are oncofetal proteins, IGF2BP2 expression is maintained in many tissues, including the heart, into adulthood. Previous studies indicated that IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodelling and returns to normal levels in recovering hearts. These results raise the possibility that IGF2BP2 might play an adaptive role during cardiac stress and recovery. Using a conditional, inducible transgenic mouse line, we found that enhanced expression of an IGF2BP2 transgene in newborn or adult hearts leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks. Downregulation of the transgene after 2 weeks, however, rescues these mice, with complete recovery by 12 weeks. Hearts overexpressing IGF2BP2 downregulate sarcomeric and mitochondrial proteins and have fragmented mitochondria and elongated, thinner sarcomeres. Consistent with these results, IGF2BP2 is upregulated in patients with DCM or after myocardial infarction. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in DCM.