Identifying new pathways to treat cardiovascular disease

The Heart Research Institute (HRI) is conducting a collaborative research project investigating new pathways to treat cardiovascular disease (CVD).

The project, called "Novel mechanisms mediating SIPS in CVD" focuses on cell senescence and CVD and is supported by a grant funded by HRI UK donors to advance research into CVD.

Assoc Prof Mary Kavurma, Vascular Complications Group leader at HRI, is collaborating with Prof Martin Bennett, British Heart Foundation Professor of Cardiovascular Sciences at the University of Cambridge, UK on this project. Prof Bennett explains the importance of this research.

Most cells in our bodies can divide, which allows new cells to be made in response to damage. Senescence means that the cells lose their ability to divide. Senescent cells have divided so many times that they become unable to do it anymore. If cells lose their ability to divide, the tissues where those cells are located may lose their ability to repair themselves if damage occurs.

Most cases of CVD are due atherosclerotic plaques, which are a build-up of fatty material inside the blood vessels. Atherosclerotic plaques can become unstable and rupture, leading to blockage of a blood vessel and the sudden onset of a heart attack or stroke. However, some plaques become more stable and less prone to rupture over time. This is due to the formation of a fibrous cap by smooth muscle cells that migrate into the plaque from the blood vessel wall.

We now know that cell senescence occurs inside atherosclerotic plaques, where it contributes to CVD. The smooth muscle cells inside the plaque are particularly likely to become senescent. If the smooth muscle cells are no longer able to divide, they have a limited ability to stabilise the plaque and stop it from rupturing.

TRAIL has a protective effect on the cardiovascular system. Low levels of TRAIL are linked to an increase in atherosclerotic plaques and a greater risk of a heart attack or stroke.

My colleague at HRI, Assoc Prof Mary Kavurma, has been working on TRAIL for many years. Mary and her team have shown that TRAIL acts as a survival factor to keep smooth muscle cells alive and continue to divide. The contribution of TRAIL to cell senescence will be examined here.

There has been a huge drive to develop drugs that alter biological ageing processes. Some of those drugs may be useful within the cardiovascular system to clear away senescent cells inside atherosclerotic plaque and rejuvenate the blood vessel wall. We believe TRAIL may also play a role and could be used as a potential therapeutic.

At the end of the project, we hope to better define the roles that TRAIL plays in cell senescence and have a better understanding of how senescent cells are cleared from atherosclerotic plaque. We also hope to identify new targets to reduce cell senescence and work out if these are viable options for treating atherosclerotic plaques. Our work is pre-clinical but is designed to lay the foundations for new treatments that we hope will benefit people with CVD.