Abstract P127: Myeloid-specific PKM2 Deletion Reduces Atherosclerosis By Limiting Inflammation

Abstract

Introduction: The underlying cause of coronary artery disease (CAD) is atherosclerosis, which is a pathological response to chronic inflammation and hyperlipidemia. The onset of atherogenesis is characterized by infiltration of myeloid cells, including monocytes followed by fatty streak formation and progressive accumulation of smooth muscle cells (SMCs). These microenvironmental changes dictate the balance between inflammatory and anti-inflammatory macrophages. Pyruvate kinase M2 (PKM2), a glycolytic enzyme, is highly expressed in activated proinflammatory macrophages. The mechanistic role of PKM2 in atherosclerosis remains unknown. Hypothesis: We hypothesize that PKM2 promotes macrophage migration in response to MCP-1 and mediates atherosclerosis by increasing inflammation. Methods and Results: PKM2 was upregulated in macrophages of Ldlr -/- mice fed a high-fat "Western" diet compared with a control chow diet. We generated the novel myeloid cell-specific PKM2 fl/fl LysMCre +/- on a Ldlr-deficient background (PKM2 fl/fl LysMCre +/- Ldlr -/- ) and evaluated atherosclerosis after 14 weeks high-fat “Western” diet feeding. Controls were littermate PKM2 fl/fl LysMCre -/- Ldlr -/- mice. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. (P<0.05, n=10-12 mice/group). Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2 -/- mice compared with control mice that was associated with decreased plasma levels of pro-inflammatory cytokines, including MCP-1, and reduced transmigration of macrophages in response to MCP-1. Macrophages isolated from myeloid-specific PKM2 -/- mice fed a high-fat "Western" diet exhibited reduced expression of pro-inflammatory genes, including MCP-1, IL-1β, IL-12, and increased expression of the anti-inflammatory genes Arg1 and IL-10. Inhibiting PKM2 nuclear translocation in bone marrow-derived macrophages led to a significant reduction in MCP-1 and IL-1β levels and reduced transmigration of macrophages. Conclusion: Genetic deletion of PKM2 in myeloid cells reduces atherosclerosis by limiting inflammation.