Overexpressed PKM2 promotes macrophage phagocytosis and atherosclerosis

Xiaochen Gai; Fangming Liu; Yuting Wu; Baohui Zhang; Bufu Tang; Kezhuo Shang; Lianmei Wang; Haihong Zhang; Yixin Chen; Shuhui Yang; Weiwei Deng; Peng Li; Jing Wang; Hongbing Zhang

doi:10.1002/ame2.12266

Overexpressed PKM2 promotes macrophage phagocytosis and atherosclerosis

Animal Model Exp Med. 2023 Apr;6(2):92-102. doi: 10.1002/ame2.12266. Epub 2022 Aug 16.

Authors

Xiaochen Gai¹, Fangming Liu¹, Yuting Wu¹, Baohui Zhang², Bufu Tang³, Kezhuo Shang¹, Lianmei Wang^{1

4}, Haihong Zhang¹, Yixin Chen⁵, Shuhui Yang¹, Weiwei Deng¹, Peng Li⁶, Jing Wang⁷, Hongbing Zhang¹

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Physiology, School of Life Science, China Medical University, Shenyang, China.
³ Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
⁵ Department of Cardiac Surgery, Fuwai Hospital, Stata Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶ School of Life Sciences, Westlake University, Hangzhou, China.
⁷ State Key Laboratory of Medical Molecular Biology, Department of Pathophysiology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Background: The expression of pyruvate kinase muscle 2 (PKM2) is augmented in macrophages of patients with atherosclerotic coronary artery disease. The role of PKM2 in atherosclerosis is to be determined.

Methods: Global and myeloid cell-specific PKM2 knock-in mice with ApoE^-/- background (ApoE^-/- , PKM2^KI/KI and Lyz2-cre, ApoE^-/- , and PKM2^flox/flox ) were produced to evaluate the clinical significance of PKM2 in atherosclerosis development. Wild-type and PKM2 knock-in macrophages were isolated to assess the function of PKM2 in macrophage phagocytosis. Atherosclerotic mice were treated with PKM2 inhibitor shikonin (SKN) to evaluate the therapeutic potential of PKM2 suppression in atherosclerosis.

Results: Oxidized low-density lipoprotein (oxLDL) upregulated PKM2 in macrophages. PKM2 in return promoted the uptake of oxLDL by macrophages. Overexpressed PKM2 accelerated atherosclerosis in mice. SKN blocked the progress of mouse atherosclerosis.

Conclusions: PKM2 accelerates macrophage phagocytosis and atherosclerosis. Targeting PKM2 is a potential therapy for atherosclerosis.

Keywords: atherosclerosis; low-density lipoprotein; macrophage; pyruvate kinase muscle 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoproteins E / metabolism
Atherosclerosis* / genetics
Atherosclerosis* / metabolism
Macrophages / metabolism
Mice
Muscles / metabolism
Phagocytosis
Pyruvate Kinase* / genetics
Pyruvate Kinase* / metabolism

Substances

Apolipoproteins E
Pyruvate Kinase
Pkm protein, mouse