Using anti-inflammatory approaches to treat hardened arteries and prevent heart disease

2018 Future Leader Fellowship

Years funded: 2019-2022

Atherosclerosis is the harmful build-up of cholesterol plaques in arteries which leads to coronary artery disease (CAD), the single leading cause of death in Australia. Inflammation contributes to formation of these plaques and is driven by accumulation of cholesterol-rich macrophages called foam cells. This makes plaques grow and become unstable, leading to arterial thrombosis and heart attack. Current treatments for CAD only partly tackle the problem of plaque inflammation, leaving unacceptably high residual disease burden. My project will study two different approaches to stop plaque inflammation and the build-up of foam cells in plaque to treat atherosclerosis.

Part 1 will investigate the repurposing of a well-established, widely available, anti-inflammatory drug called colchicine, which is used to treat gout. Colchicine has been shown in small clinical studies to possibly lower the risk of heart attack and death in people with CAD, but it is not clear how it might do so.  Based on compelling early results from my laboratory, I will study if, and how colchicine can reverse or modify plaque in mouse models of atherosclerosis, and in a study of patients with CAD who present with a heart attack. My findings will provide crucial mechanistic insights to help interpret ongoing large clinical studies of colchicine’s use in CAD, and will have major implications for whether it should be used routinely in real-world practice.

Part 2 deals with eukaryotic elongation factor 2 kinase (eEF2K), a molecule that has mainly been studied in cancer and can be blocked by drugs. I have found for the first time that eEF2K helps macrophages take up cholesterol to become foam cells. Using eEF2K knockout mice, a specific eEF2K drug inhibitor and other relevant techniques, I will study eEF2K’s role in plaque formation in mice and humans. My results will provide new information about whether eEF2K is a potential treatment target in atherosclerosis, with potential for clinical translation.

This project is co-funded with NHMRC - National Health and Medical Research Council.