Targeting GATA4 for cardiac repair.

Mika J Välimäki,Heikki J Ruskoaho

doi:10.1002/iub.2150

Abstract

Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell transplantation may eventually lead to efficient in vivo applications for the treatment of cardiac injuries, representing a novel treatment strategy for regenerative medicine. Modulation of cardiac transcription factor (TF) networks by chemical entities represents another viable option for therapeutic interventions. Comprehensive screening projects have revealed a number of molecular entities acting on molecular pathways highly critical for cellular lineage commitment and differentiation, including compounds targeting Wnt‐ and transforming growth factor beta (TGFβ)‐signaling. Furthermore, previous studies have demonstrated that GATA4 and NKX2‐5 are essential TFs in gene regulation of cardiac development and hypertrophy. For example, both of these TFs are required to fully activate mechanical stretch‐responsive genes such as atrial natriuretic peptide and brain natriuretic peptide (BNP). We have previously reported that the compound 3i‐1000 efficiently inhibited the synergy of the GATA4–NKX2‐5 interaction. Cellular effects of 3i‐1000 have been further characterized in a number of confirmatory in vitro bioassays, including rat cardiac myocytes and animal models of ischemic injury and angiotensin II‐induced pressure overload, suggesting the potential for small molecule‐induced cardioprotection.

Highlights

A network of cardiac transcription factor (TF) controls cardiac gene expression and has a central role in transcriptional regulation during cardiac differentiation and development and the adaptive pathophysiological processes in the adult heart.[1,2,3] Evolutionarily conserved cardiac TFs GATA binding protein 4 (GATA4), NK2 homeobox 5 (NKX2-5), myocyte enhancer factor 2C (MEF2C), heart and neural wileyonlinelibrary.com/journal/iubIUBMB Life. 2020;72:68–79.crest derivatives expressed 2 (HAND2), serum response factor (SRF), and T-box 5 (TBX5) have been shown to interact with and orchestrate cardiac gene expression during differentiation and development and are involved in cardiac hypertrophy in a context-dependent and dynamically evolving manner (Table 1)
We have previously reported that the compound 3i-1000 efficiently inhibited the synergy of the GATA4–NKX2-5 interaction
Increasing evidence shows that a restricted number of regulatory TFs (e.g., GATA4, HAND2, MEF2, NKX2-5, and TBX5) are required for the initiation of cardiac-like gene expression and are capable of cooperatively reprogramming cardiac fibroblasts into functional cardiac-like myocytes in vitro and in vivo.[4,5,6,7]

Summary

Introduction

A network of cardiac transcription factor (TF) controls cardiac gene expression and has a central role in transcriptional regulation during cardiac differentiation and development and the adaptive pathophysiological processes in the adult heart.[1,2,3] Evolutionarily conserved cardiac TFs GATA binding protein 4 (GATA4), NK2 homeobox 5 (NKX2-5), myocyte enhancer factor 2C (MEF2C), heart and neural wileyonlinelibrary.com/journal/iubIUBMB Life. 2020;72:68–79.crest derivatives expressed 2 (HAND2), serum response factor (SRF), and T-box 5 (TBX5) have been shown to interact with and orchestrate cardiac gene expression during differentiation and development and are involved in cardiac hypertrophy in a context-dependent and dynamically evolving manner (Table 1).

Results

Conclusion