Arteries that stay young and a lower risk of heart attack? A mission made possible by the CD38 enzyme

It is well known. Sometimes cancer treatments, whilst essential, can have adverse effects on the heart and arteries. The result: an increased risk of cardiovascular and cerebrovascular events. The problem is that, until recently, it was practically impossible to truly understand what happens within the inscrutable molecular and biochemical pathways of the body that could worsen the risk profile in such cases. Now, however, a light has been shed on the matter. Giving hope that we might soon be able to say “eureka’ is research that has identified a new, previously unseen pathway which helps explain how alterations in blood flow can promote the formation of unstable atherosclerotic plaques, which are more prone to rupture and thus to block an artery with their contents, leading to heart attacks and strokes. This is thought to occur through a reduction in the levels of protective proteins in blood vessel cells, leading to the activation of a specific senescence enzyme called CD38. It is this, ultimately, that damages the artery walls and facilitates thrombosis. This is the finding of a study by experts at the University of Texas – MD Anderson Cancer Center, published in Circulation Research. As well as helping to understand the mechanisms of cellular senescence in healthy cells linked to cancer treatments, the study points to prospects for drug therapy to limit inflammation and cellular ageing, with a possible ‘gerovital’ effect for arterial cells.

The research, coordinated by Sivareddy Kotla and Jun-ichi Abe, examined senescent cells. These cells, despite being subjected to intense stress due to the action of certain anti-cancer drugs, are no longer able to multiply but do not die. Above all, they lose key regulatory proteins, known as LATS1/2. This process then leads to the activation of the enzyme CD38, which reprogrammes the way these cells use energy and makes them more unstable. The result: inflammation of the arterial wall increases, the plaque becomes less ‘stable’, and blockages caused by the rupture of the atherosclerotic lesion—leading to a blockage in blood flow—are more likely to occur. “Our findings provide a previously unknown mechanistic link between senescence and thrombosis, which helps explain why some plaques can suddenly become dangerous,” commented Kotla in a statement. “Understanding how ageing cells reorganise their surrounding environment and trigger plaque instability is essential for the development of therapeutic strategies capable of reducing the risk of serious cardiovascular events.”

The researchers studied endothelial cells – the cells found on the inner lining of arteries – and observed that they undergo changes after ‘losing’ the LATS1/2 proteins, which normally maintain the health of these cells. Not only that: in addition to cellular ageing, plaque instability and inflammation, the researchers have shown that cells that age prematurely lead to increased levels of CD38. In experimental models, it was observed that this mechanism can lead to a reprogramming of the cell’s metabolism and energy sources: the cell must therefore consume more energy and consequently triggers inflammation, causing the plaque to destabilise. It is important to note that inhibiting CD38 reversed these effects both in vitro and in vivo. In short: although at an experimental level, it has been shown that this also occurs in human atherosclerotic plaque tissue. This suggests that there is a ‘new’ connection between blood flow patterns, cellular metabolism and vascular diseases. As Abe points out, ‘we hope that this work will open up new avenues for preventing plaque progression and thrombotic complications’.

Let’s be clear: we’re only just getting started. However, it must be said that there are already some CD38 inhibitors available for the treatment of certain types of cancer. This suggests that it may be possible to explore treatments targeting this specific pathway more readily, with the aim of stabilising plaques, limiting inflammation and controlling the risk of heart attack and stroke. “We are always seeking to better understand the mechanisms by which our blood vessels develop atherosclerosis, often beyond cholesterol levels,” comments Stefano Carugo, Professor of Cardiology and Director of Cardiology at the Policlinico di Milano. “This study appears to have identified a specific mechanism whereby, by blocking the CD38 enzyme, we can protect our arteries by stabilising atherosclerotic plaques. For now, we are talking about experimental models, but the research looks very promising, with the potential for highly significant clinical outcomes.” For the record, CD38 is a complex enzyme that plays a key role in regulating cellular and calcium metabolism and is a fundamental therapeutic target in the treatment of certain blood cancers such as multiple myeloma.