Abstract
Abstract 224: Myeloid Cell PKM2 Deletion Enhances Efferocytosis And Reduces Atherosclerosis
Arteriosclerosis, thrombosis, and vascular biology, Vol.42(Suppl_1), p.A224
05/2022
DOI: 10.1161/atvb.42.suppl_1.224
Abstract
Rationale:
The glycolytic enzyme pyruvate kinase muscle 2 (PKM2) 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.
Objective:
We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis.
Methods and Results:
We generated novel myeloid cell-specific PKM2
-/-
mice on Ldlr-deficient background (PKM2
mye-KO
Ldlr
-/-
). Controls were littermate PKM2
WT
Ldlr
-/-
mice. To rule out sex-based differences, male and female mice were placed on a high-fat "Western" diet for 14 weeks, starting at eight weeks. PKM2 was upregulated in macrophages of Ldlr
-/-
mice fed the Western diet compared with a control 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 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 pro-inflammatory genes, including MCP-1, IL-1β, and IL-12. Myeloid cell-specific PKM2
-/-
mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP1 in macrophages
in vitro
and atherosclerotic lesions
in vivo
. Silencing LRP1 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.
Conclusion:
Genetic deletion or limiting PKM2 nuclear translocation in myeloid cells reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.
Details
- Title: Subtitle
- Abstract 224: Myeloid Cell PKM2 Deletion Enhances Efferocytosis And Reduces Atherosclerosis
- Creators
- Prakash Doddapattar - University of IowaRishabh DevMadankumar Ghatge - University of IowaRakeshkumar Patel - IOWA city, IAManish Jain - University of IowaNirav Dhanesha - University of IowaSteven R Lentz - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.42(Suppl_1), p.A224
- DOI
- 10.1161/atvb.42.suppl_1.224
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2022
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984361731802771
Metrics
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