Senescence dysregulates of inflammation-resolution programs in atherosclerosis

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Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Resolution is mediated by the critical balance between specialized pro-resolving mediators (SPMs) such as lipoxins and resolvins and pro-inflammatory factors like leukotrienes (LTs) and prostaglandins (PGs). Previous work from our lab and others suggest that SPMs are defectively synthesized in plaques and that restoration of SPMs prevents atherosclerosis progression in mice. Gaps remain in our understanding as to a) what cellular processes derange the synthesis of SPMs in protective actions of SPMs in atherosclerosis. Therefore, the plaques and b) mechanisms associated with the overall objective of this proposal is to understand new mechanisms of dysregulated resolution in atherosclerosis and to harness new SPM signaling pathways towards a novel treatment strategy. Cellular senescence is an irreversible cell cycle arrest that leads to a highly pro-inflammatory phenotype called the senescence-associated secretory phenotype (SASP). Prominent features of senescent cells (SCs) include elevated levels of COX2 and PGs and heightened glycolysis. SCs recently emerged as a driver of plaque necrosis but mechanisms are poorly understood. Our new work suggests that senescence impairs endogenous resolution programs and that key SPMs can limit the SASP. We proposed a series of studies to identify the mechanisms associated with senescence and impaired resolution (Aim I), the link between myeloid senescent cells and SPM formation in plaques (Aim II) and mechanisms underlying how hypercholesterolemia impacts senescence and SPM synthesis (Aim III). The link between dysregulated resolution programs and senescence is a completely new and unexplored area of research that may reveal new treatment strategies for atherosclerosis that are complementary to those that currently exist.