The Senescence-Associated Secretory Phenotype as an Important Mechanism in Atherosclerosis

Atherosclerosis is a condition of dysfunctional macrophages. The innate immune cells called macrophages are responsible for removing cholesterol from blood vessel walls, where it lodges, carried by LDL particles. The macrophages ingest cholesterol and hand it off to HDL particles that carry it back to the liver for excretion. Macrophages exhibit packages of behaviors called polarizations, and this cleaning up of cholesterol is associated with the pro-regenerative, anti-inflammatory M2 polarization. Atherosclerosis is an inflammatory condition in the sense that chronic inflammation biases macrophages into the pro-inflammatory M1 polarization, in which they no longer attempt to clear cholesterol.

The formation of atherosclerotic lesions, fatty deposits that narrow and weaken blood vessels, occurs when macrophages are hampered enough to cross the tipping point of clearing cholesterol more slowly than it accumulates. Once a lesion forms in earnest, it becomes a toxic, inflammatory microenvironment itself, capable of overwhelming the macrophages sent to clean it up. Systemic inflammation, oxidative stress, and related body-wide issues associated with aging, obesity, and diabetes make that tipping point more easily reached.

Senescent cells contribute to chronic inflammation via the senescence-associated secretory phenotype (SASP), a mix of pro-growth, pro-inflammatory signal molecules that are harmful to tissue function when sustained over the long term. At least some of the dysfunctional macrophages present in atherosclerotic lesions are senescent, and hamper the efforts of other nearby macrophages, but the burden of senescent cells throughout the body is also a problem, given that it contributes to an environment that biases macrophages away from attempting to clear cholesterol from blood vessel walls.

The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities

The SASP contributes to the secretion of inflammatory cell cytokines and chemokines that induce local and systemic inflammatory responses, immune system activation, tissue damage and fibrosis, and cell apoptosis and dysfunction. Moreover, the SASP can also induce the enlargement of local and systemic senescence to neighbouring cells via paracrine or endocrine mechanisms. Furthermore, a variety of molecules involved in the SASP can serve as promoters and biomarkers of cardiovascular diseases including atherosclerosis.

Recent clinical trials have clearly demonstrated a causal relationship between inflammation and human atherosclerosis. Atherosclerosis is considered a chronic inflammatory disease, and atherosclerotic plaques present with cell senescence. Cell senescence and atherosclerosis have multiple common aetiological stimuli, but senescent cells are not just simple bystanders. Senescent cells from atherosclerotic plaques lack proliferation, overexpress P16INK4A, P53, P21, and increase the activity of senescence-associated beta-galactosidase (SAβG). They can also establish the SASP, which can cause increased secretion of various inflammatory cell cytokines, chemokines and matrix-degrading proteases. Notably, there is evidence that the SASP, as a source of chronic inflammation and some plaque instability factors, is involved in the pathogenesis and development of atherosclerosis.

The SASP from senescent cells exerts many pro-atherogenic effects, which may involve vascular remodelling, plaque formation and rupture. There is evidence that plaque-rich arteries contain various typical SASP components, including matrix metalloproteinases and multiple inflammatory factors. However, these phenomena are not present in normal adjacent blood vessels. Senescent cells in blood vessels with the SASP release various inflammatory cytokines (interleukin-6 and interleukin-8) and growth factors (such as VEGF, PDGF, chemokines and matrix metalloproteinases). Studies have shown that some of these are known cardiovascular risk factors. Additionally, a study reported that p16 positive cells are the main driver of the aged heart phenotype that causes a reduced lifespan in mice, so removing senescent cells with p16 promoter activity can inhibit the occurrence and development of atherosclerotic plaques and improve the stability of plaques

Therefore, the prevention of accelerated cellular senescence and the SASP represents an important therapeutic opportunity, and understanding the mechanisms responsible for this change is essential for the promotion of prevention and therapy of atherosclerosis and other age-associated diseases.

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