To what degree is it possible to slow or regress atherosclerosis by clearing senescent cells from plaque and artery walls? A few lines of evidence from animal studies suggest that slowing plaque growth is possible. These include efforts to clear senescent macrophages that have become foam cells in plaque using small molecule senolytics, or Bitterroot Bio's targeting of CD47 to achieve a similar outcome. This does not appear to produce plaque regression, however, most likely because it doesn't address the toxic cholesterol that makes up a plaque. That cholesterol will continue to attract new cells and drive those cells into dysfunction and senescence for so long as it is present.
CDKN2A/p16INK4a, a key marker of cellular senescence, is substantially upregulated during cell senescence. The elevated expression of CDKN2A inhibits the activation of CDK4 and CDK6, decreases Rb phosphorylation and blocks the G1/S transition of the mitotic cell cycle. The expression of CDKN2A increases significantly with age driven by oxidative stress and reactive oxygen species (ROS) accumulation in endothelial progenitor cells and modulates age-dependent senescence of these cells. Elimination of CDKN2A/p16INK4a-positive senescent cells has proved to be effective to attenuate age-dependent changes in several organs including kidney and heart. Therefore, CDKN2A appears to play a critical role on the onset and progression of cellular senescence. Control of CDKN2A expression is therefore a crucial mechanism for suppressing cellular senescence. To date, no studies investigated whether preventing the activation of CDKN2A and CDK4 and CDK6 pathway ameliorates vascular cellular senescence and atherogenesis in vivo and in vitro.
In our studies, β-galactosidase activity and ROS production were significantly elevated in human and mice atherosclerotic lesions. β-galactosidase, co-localized with CD31, was obviously upregulated in atherosclerotic lesions, indicating endothelial cellular senescence in vivo. CDKN2A, co-localized with CD31, was markedly increased in atherosclerotic lesions. Colocalization of CDKN2A with CDK4 and CDK6 revealed the potential connection in vivo.
Knockdown of CDKN2A counteracts endothelial cell senescence induced by oxidized LDL. CDK4 and CDK6 inhibitor palbociclib, a potent anti-proliferative agent for the treatment of breast cancer, is demonstrated to accelerate endothelial cell senescence in vitro and deteriorate atherogenesis in vivo. Our findings suggest that by ameliorating endothelial cell senescence, modulating CDKN2A and CDK4 and CDK6 pathway may represent a new highly promising strategy for the treatment of atherosclerosis.
Link: https://doi.org/10.1016/j.bcp.2025.116916
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