Removal of Senescent Foam Cells in Atherosclerosis is Beneficial

The development of unstable fatty lesions in blood vessel walls that characterizes atherosclerosis is a vicious cycle of bad cell behavior once it gets going. Cells react to the presence of damaged lipids with inflammation, and macrophages arrive in response to clean up the lipids. The macrophages ingest more damaged lipids than they can handle, turn into what are known as foam cells, call for more help, then die, and their remains contribute to the growth of the lesion and the inflammation it causes. As the research here notes, it turns out that a meaningful proportion of foam cells become senescent in the course of this process, and thus strategies that remove senescent cells in a targeted manner can slow the development of atherosclerosis in addition to all of the other benefits they produce. Senescent cells accumulate with age and cause disruption to surrounding tissue structure and cell behavior through the senescence-associated secretory phenotype (SASP), a mix of secreted signal molecules is known to provoke inflammation. In the context of what is known of atherosclerosis, it makes perfect sense that senescent cells would have an important role. Their removal is one of a number of possible points at which the vicious cycle of inflammation and immune response in atherosclerotic lesions might be sabotaged.

Cells enter a state of senescence in response to certain stresses. Studying mouse models, researchers examined the role of senescent lipid-loaded macrophages (so-called "foam cells") in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease.

Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr-/-) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.

The degredation of elastin resulting from the presence of senescent cells is an interesting point and worth dwelling on. It was also seen in a study of senescent cell removal in aged lung tissue. Loss of tissue elasticity in blood vessels is an important contribution to hypertension and consequent cardiovascular disease, but is thought to be largely a consequence of cross-linking, not cellular senescence. If it turns out that removing senescent cells significantly slows the stiffening of blood vessels with age, and perhaps this is yet another inflammatory aspect of their unwanted activity, that will probably result in an equally significant reduction in cardiovascular mortality in later life.



How can foam cells be eliminated from the body?

Posted by: Kathleen DiCioccio at January 23rd, 2023 12:42 PM

The treatments already exist - but the American medical profession keeps denying that herbs are an effective tool

Posted by: Richard Ferguson at June 28th, 2023 5:08 AM
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