Targeting dead cell clearance in vascular diseases

Dr Amy Baxter, La Trobe University

Future Leader Fellowship - Level 1

Years funded: 2025 - 2028

The role of dead cell in cardiovascular disease and diabetes

Cardiovascular disease (CVD) is the leading cause of death and disability globally, costing the Australian government >$14.3B annually. Atherosclerosis is a primary risk factor for CVD, in which plaques that form in arteries lead to life-threatening events such as heart attack and stroke. Type 2 Diabetes Mellitis (T2DM) is considered a key co-morbidity of atherosclerosis, sharing common pathological traits and impact on various body systems.

A key characteristic of both atherosclerosis and T2DM is an increase cell death in the blood vessels combined with a reduction in the body’s ability to clear dead cells. This results in the accumulation of harmful cellular waste that can cause vessel damage through the release of inflammatory proteins that prevent normal tissue repair. In atherosclerosis, this contributes to the growth of atherosclerotic plaques, increasing their risk of rupture and associated life-threatening clinical events; in diabetes, increased cell death in the small vessels of kidneys, heart, eye and brain leads to tissue damage and organ dysfunction.

Enhancing dead cell clearance within blood vessels is therefore an attractive therapeutic strategy in these vascular diseases, although there are currently no treatments clinically available.

Investigating cell clearance as a therapeutic strategy in vascular disease

Our team has recently developed a genetic mouse model of enhanced cell clearance. We will use this to examine the impact of boosting dead cell removal on plaque growth in atherosclerosis and on microvascular damage in diabetes. To complement this work, we will also use cell-based methods to characterise a novel role of endothelial cells that line blood vessels in cell clearance, expanding knowledge in the cell death and vascular biology fields. Finally, as a step towards clinical development, we will test whether an approved drug that can promote cell clearance, ‘spiramycin’, can reduce inflammation and promote vessel repair in mouse models of atherosclerosis and diabetes.

The outcomes of this study will provide proof-of-concept evidence that impaired cell clearance in these conditions can be therapeutically targeted, and form the basis of future drug development programs that aim to treat chronic vascular diseases.