PMID- 29732501
OWN - NLM
STAT- MEDLINE
DCOM- 20191014
LR  - 20191014
IS  - 1432-1440 (Electronic)
IS  - 0946-2716 (Linking)
VI  - 96
IP  - 6
DP  - 2018 Jun
TI  - PKM2-dependent metabolic reprogramming in CD4(+) T cells is crucial for 
      hyperhomocysteinemia-accelerated atherosclerosis.
PG  - 585-600
LID - 10.1007/s00109-018-1645-6 [doi]
AB  - Inflammation mediated by activated T cells plays an important role in the 
      initiation and progression of hyperhomocysteinemia (HHcy)-accelerated 
      atherosclerosis in ApoE(-/-) mice. Homocysteine (Hcy) activates T cells to 
      secrete proinflammatory cytokines, especially interferon (IFN)-gamma; however, the 
      precise mechanisms remain unclear. Metabolic reprogramming is critical for T cell 
      inflammatory activation and effector functions. Our previous study demonstrated 
      that Hcy regulates T cell mitochondrial reprogramming by enhancing endoplasmic 
      reticulum (ER)-mitochondria coupling. In this study, we further explored the 
      important role of glycolysis-mediated metabolic reprogramming in Hcy-activated 
      CD4(+) T cells. Mechanistically, Hcy-activated CD4(+) T cell increased the 
      protein expression and activity of pyruvate kinase muscle isozyme 2 (PKM2), the 
      final rate-limiting enzyme in glycolysis, via the phosphatidylinositol 
      3-kinase/AKT/mechanistic target of rapamycin signaling pathway. Knockdown of PKM2 
      by small interfering RNA reduced Hcy-induced CD4(+) T cell IFN-gamma secretion. 
      Furthermore, we generated T cell-specific PKM2 knockout mice by crossing LckCre 
      transgenic mice with PKM2(fl/fl) mice and observed that Hcy-induced glycolysis 
      and oxidative phosphorylation were both diminished in PKM2-deficient CD4(+) T 
      cells with reduced glucose and lipid metabolites, and subsequently reduced IFN-gamma 
      secretion. T cell-depleted apolipoprotein E-deficient (ApoE(-/-)) mice adoptively 
      transferred with PKM2-deficient CD4(+) T cells, compared to mice transferred with 
      control cells, showed significantly decreased HHcy-accelerated early 
      atherosclerotic lesion formation. In conclusion, this work indicates that the 
      PKM2-dependent glycolytic-lipogenic axis, a novel mechanism of metabolic 
      regulation, is crucial for HHcy-induced CD4(+) T cell activation to accelerate 
      early atherosclerosis in ApoE(-/-) mice. KEY MESSAGES: Metabolic reprogramming is 
      crucial for Hcy-induced CD4(+) T cell inflammatory activation. Hcy activates the 
      glycolytic-lipogenic pathway in CD4(+) T cells via PKM2. Targeting PKM2 
      attenuated HHcy-accelerated early atherosclerosis in ApoE(-/-) mice in vivo.
FAU - Lu, Silin
AU  - Lu S
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Deng, Jiacheng
AU  - Deng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Liu, Huiying
AU  - Liu H
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Liu, Bo
AU  - Liu B
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Yang, Juan
AU  - Yang J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Miao, Yutong
AU  - Miao Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Li, Jing
AU  - Li J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Wang, Nan
AU  - Wang N
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Jiang, Changtao
AU  - Jiang C
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China.
FAU - Xu, Qingbo
AU  - Xu Q
AD  - Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College 
      London, London, SE5 9NU, UK.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China. 
      xwang@bjmu.edu.cn.
FAU - Feng, Juan
AU  - Feng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking 
      University Health Science Center, Beijing, 100191, People's Republic of China. 
      juanfeng@bjmu.edu.cn.
LA  - eng
GR  - 91439206/National Natural Science Foundation of P. R. China/International
GR  - 81770445/National Natural Science Foundation of P. R. China/International
GR  - 2016YFC0903100/National Key Research and Development Program of 
      China/International
GR  - PKU2017LCX09/Special Program of Peking University for Clinical Medicine + 
      X/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180507
PL  - Germany
TA  - J Mol Med (Berl)
JT  - Journal of molecular medicine (Berlin, Germany)
JID - 9504370
RN  - 0 (Lipids)
RN  - 0 (RNA, Small Interfering)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 2.7.1.40 (Pkm protein, mouse)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/*metabolism
MH  - CD4-Positive T-Lymphocytes/*metabolism
MH  - Cells, Cultured
MH  - Female
MH  - Glycolysis
MH  - Homocysteine/blood
MH  - Hyperhomocysteinemia/*metabolism
MH  - Lipids/blood
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout, ApoE
MH  - Pyruvate Kinase/genetics/*metabolism
MH  - RNA, Small Interfering/genetics
OTO - NOTNLM
OT  - Atherosclerosis
OT  - CD4+ T cell
OT  - Homocysteine
OT  - Metabolic reprogramming
OT  - PKM2
EDAT- 2018/05/08 06:00
MHDA- 2019/10/15 06:00
CRDT- 2018/05/08 06:00
PHST- 2017/08/15 00:00 [received]
PHST- 2018/04/29 00:00 [accepted]
PHST- 2018/04/10 00:00 [revised]
PHST- 2018/05/08 06:00 [pubmed]
PHST- 2019/10/15 06:00 [medline]
PHST- 2018/05/08 06:00 [entrez]
AID - 10.1007/s00109-018-1645-6 [pii]
AID - 10.1007/s00109-018-1645-6 [doi]
PST - ppublish
SO  - J Mol Med (Berl). 2018 Jun;96(6):585-600. doi: 10.1007/s00109-018-1645-6. Epub 
      2018 May 7.