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Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis
Prakash Doddapattar1, Rishabh Dev1, Madankumar Ghatge1
1Division of Hematology/Oncology, Department of Internal Medicine, University of Iowa.
Background:
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.
Methods:
We generated myeloid cell-specific PKM2-/- mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2mye-KOLdlr-/-). Controls were littermate PKM2WTLdlr-/- 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.
Results:
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.
Conclusions:
Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.
Insights
Targeting pyruvate kinase muscle 2 (PKM2) in myeloid cells reduces atherosclerosis. Deleting PKM2 in these cells suppresses inflammation and enhances efferocytosis, offering a potential therapeutic strategy for cardiovascular disease.
Area of Science:
- Biochemistry
- Immunology
- Cardiovascular Biology
Background:
- Pyruvate kinase muscle 2 (PKM2) is upregulated in monocytes/macrophages in patients with atherosclerotic coronary artery disease.
- The specific role of PKM2 in myeloid cells within the context of atherosclerosis requires further elucidation.
Purpose of the Study:
- To investigate whether myeloid cell-specific PKM2 influences efferocytosis and the development of atherosclerosis.
- To explore the therapeutic potential of targeting PKM2 in atherosclerosis.
Main Methods:
- Generated myeloid cell-specific PKM2 knockout (PKM2mye-KO) mice on a low-density lipoprotein receptor (Ldlr)-deficient background.
- Evaluated atherosclerosis development in PKM2mye-KOLdlr-/- and control PKM2WTLdlr-/- mice fed a high-fat diet.
- Assessed macrophage efferocytosis, inflammatory gene expression, and glycolytic rates in isolated macrophages.
Main Results:
- Myeloid cell-specific PKM2 deletion significantly reduced atherosclerotic lesions in PKM2mye-KOLdlr-/- mice.
- PKM2 deficiency decreased macrophage infiltration, reduced monocyte chemoattractant protein 1 (MCP-1) levels, and impaired macrophage transmigration.
- Macrophages from PKM2-deficient mice showed reduced pro-inflammatory gene expression, enhanced efferocytosis, and increased LDLR-related protein-1 (LRP-1) expression.
- Inhibition of PKM2 nuclear translocation reduced atherosclerosis in vivo.
Conclusions:
- Genetic deletion of PKM2 in myeloid cells suppresses inflammation and enhances efferocytosis, thereby reducing atherosclerosis.
- Targeting PKM2, particularly its nuclear translocation, represents a promising therapeutic strategy for atherosclerosis.
