Atherosclerosis is one of the major causes of cardiovascular events, accounting for more than 50% of deaths in developed countries
Atherosclerosis
Atherosclerosis is caused by the accumulation of lipids in the walls of the arteries leading to partial or total occlusion. The etiology is multifactorial with the most risk factors being high blood cholesterol level, sedentary lifestyle, advanced age, smoking, alcohol consumption, hypertension, diabetes, positive family history, obesity, and genetic factors. One of the ways atherosclerosis can be treated is by administering lipid-lowering agents.
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It is a chronic inflammatory process involving the abnormal activation of inflammatory cells, smooth muscle cells, and endothelial cells. This process starts from the accumulation of new fat cells in the innermost wall of the artery (intima) which develops into fibrous plaques and complex atherosclerotic lesions that are prone to rupture. However, the disease process and how the risk for cardiovascular events persists despite the use of lipid-lowering drugs has not been fully understood.
Phenotypic switching
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Studies suggest that smooth muscle cells, which are part of the plaque, go on to proliferate and differentiate into other cell types. This phenomenon plays a huge role in disease progression and the development of complications. Some other genetic studies suggest that smooth muscle cells and smooth muscle cell-derived cells are the major components of atherosclerotic plaques and can either act as a protective factor or further complicate the disease. A long time ago, scientists thought that the plaques had tumor-like characteristics, however, this hasn’t been confirmed yet.
Niraparib reduces atherosclerotic plaques
Huize Pan and his colleagues conducted a study further investigating these suggestions and they found out that atherosclerotic plaques have similarities with tumor cells. They went ahead to apply smooth muscle cell lineage tracking in mice and carried out molecular, cellular, histological, computational, genetic, and pharmaceutical analyses.
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They discovered genomic instability, activation of oncogenic pathways, characteristics resembling tumor cells, smooth muscle cell proliferation and differentiation driven by oncogenes, and most significantly, positive response to anti-cancer treatment.
The administration of the anti-cancer drug, niraparib (Zejula), caused reduced smooth muscle cell phenotypic switching by inducing oxidative DNA damage and also reduced smooth muscle cell-derived lineage cells. It reduced atherosclerotic plaques in the aorta and decreased necrotic core area. Evidence has shown that anti-cancer therapy can induce some atheroprotective properties like the inhibition of cell proliferation and macrophage phagocytosis.
Clinical significance
These findings agree with the previous suggestions that atherosclerotic plaques have tumor-like features. Henceforth, anti-cancer therapies can be applied as a therapeutic strategy against atherosclerosis.
However, not all cancer therapies are beneficial. Some treatment strategies like immunotherapy that cause the blocking of PD1/PD-L1, can increase the risk of cardiovascular events by stimulating cytotoxic T cells to secret atherogenic cytokines.
More studies still need to be carried out, especially the ones that focus on the molecular and genetic pathways involving atherosclerosis and cancer. However, these findings present new opportunities in the management of atherosclerosis.
References
Pan, H., Ho, S. E., Xue, C., Cui, J., Johanson, Q. S., Sachs, N., Ross, L. S., Li, F., Solomon, R. A., Connolly, E. S. Jr., Patel, V. I., … (2024). Atherosclerosis is a smooth muscle cell–driven tumor-like disease. Circulation, 149(1885-1898). https://doi.org/10.1161/CIRCULATIONAHA.123.067587
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