PMID- 35400205
OWN - NLM
STAT- MEDLINE
DCOM- 20220502
LR  - 20240327
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 130
IP  - 9
DP  - 2022 Apr 29
TI  - Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.
PG  - 1289-1305
LID - 10.1161/CIRCRESAHA.121.320704 [doi]
AB  - 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 (PKM2(mye-KO)Ldlr(-/-)). Controls were littermate 
      PKM2(WT)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. 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)-1beta, 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.
FAU - Doddapattar, Prakash
AU  - Doddapattar P
AUID- ORCID: 0000-0003-4219-5240
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Dev, Rishabh
AU  - Dev R
AUID- ORCID: 0000-0002-7878-6934
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Ghatge, Madankumar
AU  - Ghatge M
AUID- ORCID: 0000-0002-6606-0108
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Patel, Rakesh B
AU  - Patel RB
AUID- ORCID: 0000-0001-9727-9738
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Jain, Manish
AU  - Jain M
AUID- ORCID: 0000-0002-7263-9829
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Dhanesha, Nirav
AU  - Dhanesha N
AUID- ORCID: 0000-0001-9268-4363
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Lentz, Steven R
AU  - Lentz SR
AUID- ORCID: 0000-0002-8885-4718
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
FAU - Chauhan, Anil K
AU  - Chauhan AK
AUID- ORCID: 0000-0001-8554-0898
AD  - Division of Hematology/Oncology, Department of Internal Medicine, University of 
      Iowa.
LA  - eng
GR  - R01 NS109910/NS/NINDS NIH HHS/United States
GR  - R35 HL139926/HL/NHLBI NIH HHS/United States
GR  - U01 NS113388/NS/NINDS NIH HHS/United States
GR  - U24 NS107247/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220411
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Receptors, LDL)
RN  - EC 2.7.1.40 (Pkm protein, mouse)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Animals
MH  - Aorta/metabolism
MH  - *Atherosclerosis/genetics/metabolism/prevention & control
MH  - Female
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Cells/metabolism
MH  - Phagocytosis
MH  - Pyruvate Kinase/*metabolism
MH  - *Receptors, LDL/metabolism
PMC - PMC9050913
MID - NIHMS1792989
OTO - NOTNLM
OT  - atherosclerosis
OT  - gene expression
OT  - inflammation
OT  - macrophages
OT  - pyruvate kinase
EDAT- 2022/04/12 06:00
MHDA- 2022/05/03 06:00
PMCR- 2023/04/29
CRDT- 2022/04/11 05:23
PHST- 2022/04/12 06:00 [pubmed]
PHST- 2022/05/03 06:00 [medline]
PHST- 2022/04/11 05:23 [entrez]
PHST- 2023/04/29 00:00 [pmc-release]
AID - 10.1161/CIRCRESAHA.121.320704 [doi]
PST - ppublish
SO  - Circ Res. 2022 Apr 29;130(9):1289-1305. doi: 10.1161/CIRCRESAHA.121.320704. Epub 
      2022 Apr 11.