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, University of Cambridge on this project. Prof Bennett explains the importance of this research.
What is cell senescence?
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.
What can lead to cell senescence?
Environmental stresses can cause senescence - stress-induced premature senescence (SIPS).
All the factors that we consider as risk factors for CVD - smoking, diabetes, high blood pressure - act as environmental stressors. These risk factors place stress on the cells, leading to early (premature) senescence.
It may help to think of cells and tissues in the body as having two "ages" - a chronological age and a biological age. Chronological age relates to the number of years the body is alive. Biological age relates to the additional stresses and strains that parts of the body experience during that time. Some parts of the body may have a more advanced biological age compared to their chronological age. Cell senescence is part of that biological ageing process.
L-R: Prof Martin Bennett, University of Cambridge, and Assoc Prof Mary Kavurma, HRI
How does cell senescence contribute to CVD?
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.
What role does TRAIL play?
We have shown that a substance called TRAIL is linked to atherosclerosis.
TRAIL is a protein that binds to the cell through receptors on its outer surface. In many cases, when TRAIL binds to the cell surface it triggers a process that kills the cell. However, TRAIL can bind to a number of different receptors, which allow it to have different effects depending on which receptors are present on the cell surface.
The funding that we have been awarded from donors in the UK will help us to better understand how TRAIL works and what it does to senescent cells.
What effect does TRAIL have on the cardiovascular system?
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.
How might this work help people at risk of heart attack or stroke?
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.
What do you hope to have achieved at the end of this two-year project?
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.
How will the HRI UK grant help progress this research?
There is a long-standing collaboration between Assoc Prof Kavurma, and her team at HRI, and my team at the University of Cambridge. We focus on the same problems - coronary heart disease and stroke - but approach them from different directions. This funding will allow us to bring together our two teams, with their complementary strengths and expertise, to form a multidisciplinary team.
We are incredibly grateful to HRI and to the people in the UK whose donations are funding this work. CVD is a truly international problem; it is the biggest killer in many countries across the world. However, it is difficult to find funding opportunities that will support collaborative work between researchers in different countries. The funding from HRI and its donors will harness the strengths of researchers across the globe to tackle CVD.
