ENDOTHELIAL GATA4 IN ATHEROSCLEROSIS PROGRESSION

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Atherosclerosis is a disease of arteries that is a leading cause of death. It is characterised by the build-up of fatty deposits called plaques. Some plaques develop into dangerous forms that can rupture leading to heart attack or stroke. This process is driven by complex blood flow patterns at bends or branches of arteries. The mechanisms of this link, which are currently unknown, could inform new therapies to prevent plaque rupture. To elucidate them, we used an unbiased approach to identify and characterise flow-responsive genes and found that the transcription factor GATA4 was unique in driving multiple processes (inflammation, proliferation, apoptosis) that are known to promote plaque rupture. The proposed work brings together a group of basic scientists and clinicians to test the hypothesis that GATA4 is a master regulator of endothelial pathogenic change and that targeting of the GATA4 pathway can reduce the risk of rupture in diseased arteries. We propose an ambitious project of research including the use of conditional knockouts in mice and analysis of human coronary artery plaques to determine the role of endothelial GATA4 in driving plaque progression towards dangerous rupture-prone forms. Importantly, the GATA4 pathway has not been studied previously in atherosclerotic plaques and it therefore represents a novel and valuable resource in terms of potential new drug targets. Indeed, we propose to identify molecular targets in the GATA4 pathway that may be amenable to pharmacological modulation and can be followed-up in future studies. The proposed research project has high potential impact because it will lead to the identification of molecular targets in the GATA4 pathway that can be targeted to reduce the risk of plaque rupture, benefiting patients at risk of heart attack or stroke.