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Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis
Journal article   Open access   Peer reviewed

Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis

Prakash Doddapattar, Rishabh Dev, Madankumar Ghatge, Rakesh B Patel, Manish Jain, Nirav Dhanesha, Steven R Lentz and Anil K Chauhan
Circulation research, Vol.130(9), pp.1289-1305
04/29/2022
DOI: 10.1161/CIRCRESAHA.121.320704
PMCID: PMC9050913
PMID: 35400205
url
https://doi.org/10.1161/CIRCRESAHA.121.320704View
Published (Version of record) Open Access

Abstract

The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis. We generated myeloid cell-specific PKM2 mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2 Ldlr ). Controls were littermate PKM2 Ldlr mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high-fat Western diet for 14 weeks, starting at 8 weeks. PKM2 was upregulated in macrophages of Ldlr mice fed a high-fat Western diet compared with chow diet. 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. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2 mice associated with decreased MCP-1 (monocyte chemoattractant protein 1) levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2 mice fed the Western diet exhibited reduced expression of proinflammatory genes, including MCP-1, IL (interleukin)-1β, and IL-12. Myeloid cell-specific PKM2 mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP (LDLR-related protein)-1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP-1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr mice. Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.
 Animals Aorta - metabolism Atherosclerosis - genetics Atherosclerosis - metabolism Atherosclerosis - prevention & control Female Humans Macrophages - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cells - metabolism Phagocytosis Receptors, LDL - metabolism

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