Abstract 13: Macrophage Erk5 Activation Induced by Apoptotic Cells and Statins Promotes Efferocytosis and Inhibits Atherosclerosis Formation

Abstract

Backgrounds Defective efferocytosis (phagocytic clearance of dying cells) is critically linked to progression of advanced atherosclerotic lesions. Although it has been well known that efferocytosis is processed by molecules including eat-me and find-me signals, it is unclear how efferocytosis becomes defective in advanced lesion. Methods and Results Here, we found that bone marrow-derived macrophages (BMDM) from macrophage-specific ERK5 knockout (ERK5 fl/fl LysM Cre +/- ; ERK5-MKO) mice reduced mRNA and proteins levels of efferocytosis-related signaling molecules such as Mer-tK, C1qa, C1qb, C1qc, Gas6, Mfg-e8, Thbs1, and Anxa1 compared with BMDM from non-transgenic control (NLC) mice. Interestingly, addition of apoptotic cells and pitavastatin activate ERK5 kinase activity and increase opsonins, eat-me and find-me signals, and phagocytic capacity toward apoptotic cells in normal macrophage, but macrophages from ERK5-MKO failed to respond in this manner. ERK5-MKO crossed to LDLR -/- mice and fed a high cholesterol diet for 16-week accelerated atherosclerosis formation with an increased level of apoptotic cell accumulation and necrotic core formation, which was accompanied by a significant reduction in collagen content and fibrous cap thickness. We also found lower levels of expression for Mfg-e8 and Thbs1 in the advanced necrotic core of ERK5-MKO mice compared to NLC mice. Conclusion Our study shows that apoptotic cells and statins-activated ERK5 plays a key role in coordinating the process of efferocytosis. Our results provide a mechanistic understanding of the clinically well-described cardiac risk of acute atherothrombotic events in advanced lesions. 1