Abstract
Heart failure, a progressive disease, is a consequence of various cardiac diseases. It is one of the leading causes of mortality in the world and a challenge for modern medicine. Although the primary prevention of cardiac diseases in developed countries has improved, the absolute number of heart failure patients is increasing. The current treatments relieve the symptoms and improve quality of life, but they only delay the progression of the disease.
Cardiac hypertrophy initially develops as an adaptive response to reduce ventricular wall stress and maintain cardiac function. However, if hypertrophy is prolonged, it activates pathological remodelling processes, e.g. increased fibrosis and cell death, inadequate angiogenesis and upregulation of foetal gene expression. Sequence-specific DNA-binding proteins, transcription factors (TFs), regulate gene expression and coordinate cell specification. The TF GATA-binding protein 4 (GATA4) is involved in several remodelling processes. It mediates the hypertrophic growth of cardiomyocytes, induces angiogenesis, and regulates apoptosis and cell survival. GATA4 and another cardiac TF, NK2 homeobox 5 (NKX2-5), interact physically and synergistically upregulate gene expression of, e.g. the foetal genes. In addition, their physical co-operation is required for mechanical stretch-induced brain natriuretic peptide (BNP) activation and cardiomyocyte hypertrophy. Thus, GATA4-NKX2-5 interaction is an interesting novel drug target.
The aim of this thesis was to (i) characterise the GATA4-NKX2-5 protein-protein interaction and determine the NKX2-5 binding site on the GATA4 protein, (ii) investigate small molecule binding to GATA4 and NKX2-5 and (iii) to study the effect of the small molecule compounds in experimental in vivo models of heart failure. Mutational studies revealed a specific region involving amino acid N272 on the surface of the GATA4 protein that mediates the interaction with NKX2-5. The inhibitor of GATA4-NKX2-5 interaction, 3i-1000, was demonstrated to bind GATA4. This compound presented anti-hypertrophic and cardioprotective effects in vivo. This work demonstrates that cardiac TFs can be targeted and their functions modulated with small molecule compounds. In addition, the results suggest that targeting protein-protein interactions of key TFs may present a novel strategy for treatment of heart failure.
Cardiac hypertrophy initially develops as an adaptive response to reduce ventricular wall stress and maintain cardiac function. However, if hypertrophy is prolonged, it activates pathological remodelling processes, e.g. increased fibrosis and cell death, inadequate angiogenesis and upregulation of foetal gene expression. Sequence-specific DNA-binding proteins, transcription factors (TFs), regulate gene expression and coordinate cell specification. The TF GATA-binding protein 4 (GATA4) is involved in several remodelling processes. It mediates the hypertrophic growth of cardiomyocytes, induces angiogenesis, and regulates apoptosis and cell survival. GATA4 and another cardiac TF, NK2 homeobox 5 (NKX2-5), interact physically and synergistically upregulate gene expression of, e.g. the foetal genes. In addition, their physical co-operation is required for mechanical stretch-induced brain natriuretic peptide (BNP) activation and cardiomyocyte hypertrophy. Thus, GATA4-NKX2-5 interaction is an interesting novel drug target.
The aim of this thesis was to (i) characterise the GATA4-NKX2-5 protein-protein interaction and determine the NKX2-5 binding site on the GATA4 protein, (ii) investigate small molecule binding to GATA4 and NKX2-5 and (iii) to study the effect of the small molecule compounds in experimental in vivo models of heart failure. Mutational studies revealed a specific region involving amino acid N272 on the surface of the GATA4 protein that mediates the interaction with NKX2-5. The inhibitor of GATA4-NKX2-5 interaction, 3i-1000, was demonstrated to bind GATA4. This compound presented anti-hypertrophic and cardioprotective effects in vivo. This work demonstrates that cardiac TFs can be targeted and their functions modulated with small molecule compounds. In addition, the results suggest that targeting protein-protein interactions of key TFs may present a novel strategy for treatment of heart failure.
Original language | Finnish |
---|---|
Print ISBNs | 978-952-62-2610-1 |
Electronic ISBNs | 978-952-62-2611-8 |
Publication status | Published - 5 May 2020 |
MoE publication type | G5 Doctoral dissertation (article) |
Fields of Science
- 3121 General medicine, internal medicine and other clinical medicine