ENDOTHELIAL GATA4 IN ATHEROSCLEROSIS PROGRESSION

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.

Background. Disturbed blood flow promotes rupture of atherosclerotic plaques which causes myocardial infarction and stroke. The mechanisms of this link were unknown but we recently demonstrated a role for the transcription factor GATA4 which is induced by disturbed flow and abundantly expressed in plaque endothelial cells (EC). We found that GATA4 amplifies atherosclerosis and drives multiple pathogenic changes in EC that are known to promote plaque rupture (inflammation, excessive proliferation and apoptosis). We hypothesize that GATA4 is a master regulator of EC pathogenic change and an essential driver of plaque progression towards rupture.

Scientific objectives. We will define the role of GATA4 and its downstream targets in the progression of atherosclerotic plaques towards rupture. GATA4 is pleiotropic with the ability to induce divergent transcriptional programmes that vary according to cell type, and we therefore propose to identify transcriptional targets of GATA4 that specifically play a role in atherosclerosis but are not involved in tissue homeostasis.

Plan of investigation. The role of endothelial GATA4 in atheroprogression will be elucidated using human coronary artery plaques and conditional knockout approaches in mice. We will identify GATA4 gene regulatory networks controlling EC pathogenic changes by single cell RNAseq analysis. To focus on mechanisms that are exclusively pathogenic, we will deselect GATA4 networks involved in homeostasis.

Potential future applications. The proposed research will elucidate GATA4 gene regulatory networks that are specifically involved in atherosclerosis progression, thereby identifying molecules that could be safely targeted to benefit patients at risk of myocardial infarction or stroke. 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.