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Published on: May 21, 2020
RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy
Miriam Krumbein1, Froma Oberman1, Yuval Cinnamon2
1Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
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. IGF2BP2 is upregulated in cardiomyocytes during cardiac stress and remodeling and returns to normal levels in recovering hearts. We wondered whether IGF2BP2 might play an adaptive role during cardiac stress and recovery. Enhanced expression of an IGF2BP2 transgene in a conditional, inducible mouse line leads to dilated cardiomyopathy (DCM) and death within 3-4 weeks in newborn or adult hearts. 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. IGF2BP2 is also upregulated in DCM or myocardial infarction patients. These results suggest that IGF2BP2 may be an attractive target for therapeutic intervention in cardiomyopathies.
Insights
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) causes dilated cardiomyopathy when overexpressed in mice. However, reducing IGF2BP2 levels rescues heart function, suggesting it
Area of Science:
- Molecular and Cellular Biology
- Cardiovascular Research
- RNA Biology
Background:
- The Insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family comprises three paralogs involved in RNA regulation.
- While IGF2BP1 and IGF2BP3 are oncofetal proteins, IGF2BP2 persists in adult tissues, including the heart.
- IGF2BP2 levels increase in cardiomyocytes during cardiac stress and remodeling.
Purpose of the Study:
- To investigate the adaptive role of IGF2BP2 during cardiac stress and recovery.
- To determine the functional consequences of IGF2BP2 overexpression in the heart.
Main Methods:
- Utilized a conditional, inducible mouse model with enhanced IGF2BP2 expression.
- Administered transgene downregulation to assess recovery.
- Analyzed cardiac structure, sarcomeres, and mitochondrial morphology.
Main Results:
- Overexpression of IGF2BP2 in mice led to dilated cardiomyopathy (DCM) and mortality.
- Downregulation of IGF2BP2 expression rescued mice, enabling complete cardiac recovery.
- Hearts overexpressing IGF2BP2 showed reduced sarcomeric and mitochondrial proteins, fragmented mitochondria, and altered sarcomere structure.
Conclusions:
- IGF2BP2 plays a critical role in cardiac function and pathology.
- Elevated IGF2BP2 levels are associated with cardiomyopathies in both mouse models and human patients.
- IGF2BP2 represents a potential therapeutic target for treating cardiomyopathies.
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