RNA Binding Protein IGF2BP2 Identified as Key Player in Stress-Induced Dilated Cardiomyopathy

RNA Binding Protein IGF2BP2 Identified as Key Player in Stress-Induced Dilated Cardiomyopathy
14th December 2023 Moriah Aharon

Researchers from Hebrew University, Hadassah Medical Center and Martin-Luther University Halle-Wittenburg Uncover Critical Role of IGF2BP2 in Cardiac Stress Response. The research uncovers the role of IGF2BP2, an RNA binding protein, in responding to cardiac stress. It highlights how heightened expression of IGF2BP2 leads to dilated cardiomyopathy (DCM) and subsequent mortality, yet a controlled reduction in expression prompts a recovery, hinting at its potential reversibility. The study also links increased IGF2BP2 levels in patients with DCM or myocardial infarction, suggesting clinical relevance. These findings offer a new understanding of stress-induced cardiomyopathy and open doors for innovative therapeutic strategies, positioning IGF2BP2 as a promising target for treating various heart conditions, potentially transforming patient care in this domain.

[Jerusalem, Israel] – A new study has unveiled a discovery regarding the role of RNA binding protein IGF2BP2 in stress-induced heart conditions.

The IGF2BP family of RNA binding proteins, known for their regulatory influence on intracellular RNA dynamics, has long intrigued researchers. While IGF2BP1 and 3 have been associated with oncofetal properties, IGF2BP2 stands out for its sustained expression in numerous tissues, particularly in the heart throughout adulthood.

This study focuses on IGF2BP2’s response in cardiomyocytes during periods of cardiac stress and remodelling. Researchers observed an elevation in IGF2BP2 expression under stress conditions, followed by a return to baseline levels during cardiac recovery. This pattern prompted the investigation into the potential adaptive role of IGF2BP2 in managing cardiac stress.

Utilising an inducible mouse line with enhancible IGF2BP2 expression, researchers observed a unexpected outcome: elevated IGF2BP2 expression inevitably leads to dilated cardiomyopathy (DCM) of the heart and subsequent mortality within 3-4 weeks in both newborns and adults. However, if transgene expression was downregulated within two weeks, a rescue effect ensued. None of the mice died, and complete recovery was observed within 12 weeks, indicating the potential for reversibility in this condition.

Further analysis of hearts exhibiting heightened IGF2BP2 levels revealed notable changes in sarcomeric and mitochondrial proteins. Specifically, these hearts displayed characteristics such as fragmented mitochondria and elongated, thinner sarcomeres, shedding light on the underlying mechanisms contributing to DCM.

Importantly, the research team also identified heightened levels of IGF2BP2 in patients diagnosed with DCM or myocardial infarction, suggesting clinical relevance and the potential for targeted therapeutic interventions.

The prevalence of DCM is a matter of debate but has been estimated to be as high as 1 in 250 adults. Prof. Joel Yisraeli, the principle investigator on the project, from the Institute for Medical Research-Israel–Canada at Hebrew University, remarked, “These findings unlock a previously undiscovered role for IGF2BP2 in stress-induced cardiomyopathy, paving the way for innovative therapeutic strategies in managing heart conditions.”

The results were recently published, with Dr. Miriam Krumbein as lead author, in Communications Biology, a Nature Portfolio journal, as part of a collaborative effort between the Yisraeli lab in the Institute for Medical Research – Israel-Canada at the Hebrew University of Jerusalem, and Prof. Sonja Kessler of the Martin-Luther University Halle-Wittenburg.

This discovery underscores the potential of IGF2BP2 as a promising therapeutic target for various cardiomyopathies. The team’s findings offer new avenues for research and potential treatment breakthroughs, heralding hope for individuals affected by heart-related ailments.

The research paper titled “RNA binding protein IGF2BP2 expression is induced by stress in the heart and mediates dilated cardiomyopathy” is now available and can be accessed here.

Miriam Krumbein1, Froma Oberman1, Yuval Cinnamon2, Mordechai Golomb3, Dalit May4, Gilad Vainer5, Vitali Belzer5, Karen Meir5, Irina Fridman1, Johannes Haybaeck6,7, Gerhard Poelzl8, Izhak Kehat9, Ronen Beeri10, Sonja M. Kessler11 & Joel K. Yisraeli1

1) Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel–Canada, Faculty of Medicine, Hebrew University of Jerusalem
2) Institute of Animal Science, Agricultural Research Organization, The Volcani Institute, Rishon Lezion
3) The Heart Institute, Hadassah Medical Center
4) Faculty of Medicine, The Hebrew University of Jerusalem, Shaare Zedek Medical Center
5) Department of Pathology, Hadassah Medical Center, Jerusalem, Israel
6) Institut für Pathologie, Neuropathologie und Molekularpathologie, Medical University Innsbruck, Innsbruck, Austria
7) Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Austria
8) Department of Cardiology and Angiology, Medical University Innsbruck, Innsbruck, Austria
9) Department of Physiology and Biophysics, The Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology
10) Department of Cardiology, Hadassah Medical Center, Jerusalem
11) Experimental Pharmacology for Natural Sciences, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany

Title: Development of dilated cardiomyopathy in mice expressing IGF2BP2
Caption: Hearts expressing transgenic IGF2BP2 become enlarged and develop DCM within 3-4 weeks.
Credit: Miriam Krumbein

Hearts expressing transgenic IGF2BP2 become enlarged and develop DCM within 3-4 weeks.

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