The interaction of transcription factors GATA4 and NKX2-5 and the effect of interaction-targeted small molecules on the heart

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Remote connection: http://video.helsinki.fi/unitube/live-stream.html?room=l17

Topic of the dissertation

The interaction of transcription factors GATA4 and NKX2-5 and the effect of interaction-targeted small molecules on the heart

Doctoral candidate

Master of Science Sini Kinnunen

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine

Subject of study

Pharmacology and Toxicology

Opponent

Professor Markku Heikinheimo, University of Helsinki

Custos

Professor Heikki Ruskoaho, University of Helsinki

Add event to calendar

Proteins regulating gene expression as a potential drug target in heart failure

The protein-protein interaction of two key proteins (transcription factors) regulating gene expression in abnormal cardiac enlargement and heart failure was characterised. This led to discovery of small molecule compounds interfering protein-protein interaction. One of the most promising compounds reduced abnormal remodelling of the cardiomyocytes in cell culture and presented cardioprotective effects in small animal models of heart failure.

Heart failure is a clinical syndrome where the heart is unable to pump sufficiently to maintain blood flow for the needs of the body. It is a consequence of various cardiac diseases, mainly coronary heart disease, high blood pressure, valve dysfunction or myocardial infarction. In the early stage of these cardiac diseases, heart grows in size, also called as left ventricular hypertrophy. This may be beneficial in the beginning, however, if prolonged the cardiac muscle will expand and stiffs, resulting insufficient pumping function.

Overall 1-2% of the adult population have heart failure; however, in those over the age of 75, every tenth has this disease. The typical symptoms are breathlessness, ankle swelling and fatigue.

For treatment of heart failure several drugs are used, most importantly, diuretics, ACE inhibitors, angiotensin receptor blockers and beta-blockers. The current medicines relieve the symptoms; however, they only delay the progression of the disease. Thus, new approaches are needed to enhance the pharmacotherapy of heart failure.

This study brought new information about the interaction of the two key proteins regulating cardiac gene expression and led to discovery of small molecule compounds targeted to interaction. In addition, the binding of the most promising compound to target proteins was studied. The results suggest that modulation of the gene regulatory proteins involved in cardiac hypertrophy may present a novel strategy for the treatment of heart failure.
Last updated: 7.5.2020