Abstract 450: Map Kinase Phosphatase-5 Deficiency Impairs Efferocytosis And Exacerbates Late-Stage Atherosclerosis

Objective: Atherosclerosis is a vascular inflammatory disease that is the leading cause of death worldwide. Late-stage atherosclerotic plaque contains a thin fibrous cap and a large necrotic core that is prone to rupture. Efferocytosis contributes to the clearance of apoptotic cells within the early plaque but is impaired in late-stage atherosclerosis, promoting rupture. MAPK phosphatase-5 (MKP-5) is crucial in regulating various processes, including inflammatory diseases and cardiac fibrosis. The goal of this project is to identify the role of MKP-5 in late-stage atherosclerotic plaque stability. Results: To induce late-stage atherosclerosis, we used a novel late-stage atherosclerosis model that leads to coronary artery lesions, plaque rupture, and spontaneous myocardial infarction. 9-week-old male and female LDLR -/- and LDLR -/- MKP-5 -/- mice were subjected to transverse aortic constriction pressure overload surgery and fed a high-fat diet (western diet with 1.25% cholesterol) for 12 weeks. Our data show that MKP-5 deficiency exacerbates plaque instability, including decreased cap thickness, increased necrosis in the atherosclerotic plaque, severe coronary lesions, as well as higher instances of intraplaque hemorrhage in the right carotids. Mechanistically, TUNEL staining of the aortic roots was performed to determine efferocytotic capabilities. Results showed fewer macrophage-associated TUNEL-positive cells in LDLR -/- MKP-5 -/- mice aortic roots, which indicates defective efferocytosis. Furthermore, bone-marrow-derived macrophages (BMDMs) isolated from WT and MKP-5 -/- mice were incubated with labeled apoptotic cells and then subsequently analyzed to determine efferocytotic capabilities. Results showed that efferocytosis was significantly inhibited in MKP-5 -/- BMDMs. Additionally, RT-PCR analysis revealed that the expression of efferocytotic receptors in MKP-5 -/- BMDMs were decreased. RNAseq analysis was performed on WT and MKP-5 -/- BMDMs stimulated with ox-LDL, identifying pathways regulated by MKP-5. Conclusions: Our study suggests that MKP-5 deficiency decreases the stability of the late-stage plaque and exacerbates atherosclerosis through impaired efferocytosis.