Abstract 002: Resolvin D1 Limits Senescent Cells in Atherosclerosis

Abstract

Non-resolving inflammation is the underpinning of several prevalent diseases including atherosclerosis. Understanding new mechanisms to promote the resolution of inflammation in atherosclerosis are of interest. Resolution is mediated by resolvins, including Resolvin D1 (RvD1). We recently showed that RvD1 prevents lesional necrosis in Ldlr -/- mice. However, the mechanisms underlying RvD1’s protective actions remain unknown. In this regard, the accumulation of senescent cells (SCs) was recently shown to promote necrotic core formation in Ldlr -/- mice. SCs are harmful because they possess a pro-inflammatory and proteolytic phenotype called the senescence associated secretory phenotype (SASP). Because RvD1 decreased lesional necrosis, we questioned whether RvD1’s actions were through limiting SCs in plaques. First, we found that human symptomatic plaques had significantly less RvD1 and significantly more SCs (quantified by positive p16 INK4A immunofluorescence staining) compared with asymptomatic plaques. To prove causation, we administered RvD1 to Ldlr -/- mice during advanced atherosclerosis and observed a significant decrease in lesional SCs and necrosis compared with vehicle controls. Mechanistically, we found that RvD1 significantly decreased the SASP as well as beta-galactosidase and p16 INK4A in WI-38 senescent cells. Importantly, a major component of the SASP is ADAM17, which is an enzyme that cleaves (and thus inactivates) a critical efferocytosis receptor on macrophages called MerTK. Because SCs are not cleared in plaques we questioned whether the SASP deranges efferocytosis mechanisms via their ability to cleave MerTK on macrophages. To investigate whether MerTK cleavage deranges SC clearance in plaques, we transplanted bone marrow from wild type (WT) or MerTK cleavage resistant (Mertk CR ) mice into Ldlr -/- mice, and quantified the levels of lesional p16 INK4A after 12 weeks of Western Diet feeding. Mertk CR mice had significantly less p16 INK4A levels and smaller necrotic cores compared with WT controls. Overall, we identified new functions for RvD1 and uncovered, for the first time, an endogenous mechanism for SC clearance. Our findings may provide new therapeutic strategies to treat atherosclerosis.