PMID- 28947430
OWN - NLM
STAT- MEDLINE
DCOM- 20171127
LR  - 20211204
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Print)
IS  - 0009-7322 (Linking)
VI  - 136
IP  - 21
DP  - 2017 Nov 21
TI  - SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.
PG  - 2051-2067
LID - 10.1161/CIRCULATIONAHA.117.028728 [doi]
AB  - BACKGROUND: Pathological cardiac hypertrophy induced by stresses such as aging 
      and neurohumoral activation is an independent risk factor for heart failure and 
      is considered a target for the treatment of heart failure. However, the 
      mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We 
      aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang 
      II)-induced pathological cardiac hypertrophy. METHODS: Male C57BL/6J wild-type 
      and Sirt2 knockout mice were subjected to the investigation of aging-related 
      cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d 
      for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 
      transgenic (SIRT2-Tg) mice, and their respective littermates (8 to  approximately 12 weeks 
      old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice 
      infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were 
      examined in these mice. RESULTS: SIRT2 protein expression levels were 
      downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly 
      exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection 
      fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused 
      mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts 
      against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac 
      function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein 
      kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as 
      in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major 
      upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and 
      deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the 
      subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 
      blunted the response of AMPK to metformin treatment in mice infused with Ang II 
      and repressed the metformin-mediated reduction of cardiac hypertrophy and 
      protection of cardiac function. CONCLUSIONS: SIRT2 promotes AMPK activation by 
      deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes 
      aging-related and Ang II-induced cardiac hypertrophy, and blunts 
      metformin-mediated cardioprotective effects. These findings indicate that SIRT2 
      will be a potential target for therapeutic interventions in aging- and 
      stress-induced cardiac hypertrophy.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Tang, Xiaoqiang
AU  - Tang X
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Chen, Xiao-Feng
AU  - Chen XF
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Wang, Nan-Yu
AU  - Wang NY
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Wang, Xiao-Man
AU  - Wang XM
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Liang, Shu-Ting
AU  - Liang ST
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Zheng, Wei
AU  - Zheng W
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Lu, Yun-Biao
AU  - Lu YB
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Zhao, Xiang
AU  - Zhao X
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Hao, De-Long
AU  - Hao DL
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Zhang, Zhu-Qin
AU  - Zhang ZQ
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.).
FAU - Zou, Ming-Hui
AU  - Zou MH
AD  - Center for Molecular and Translational Medicine, Georgia State University, 
      Atlanta (M.-H.Z).
FAU - Liu, De-Pei
AU  - Liu DP
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.) 
      chenhouzao@ibms.cams.cn liudp@pumc.edu.cn.
FAU - Chen, Hou-Zao
AU  - Chen HZ
AD  - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical 
      Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of 
      Medical Sciences and Peking Union Medical College, Beijing (X.T., X.-F.C., 
      N.-Y.W., X.-M.W., S.-T.L., W.Z., X.Z., D.-L.H., Z.-Q.Z., H.-Z.C., D.-P.L.) 
      chenhouzao@ibms.cams.cn liudp@pumc.edu.cn.
LA  - eng
GR  - R01 HL080499/HL/NHLBI NIH HHS/United States
GR  - R01 HL089920/HL/NHLBI NIH HHS/United States
GR  - R01 HL132500/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20170925
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Sirt2 protein, rat)
RN  - 11128-99-7 (Angiotensin II)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.1 (Stk11 protein, rat)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.5.1.- (Sirt2 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 2)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Acetylation
MH  - Age Factors
MH  - Aging/metabolism
MH  - Angiotensin II
MH  - Animals
MH  - Cardiomegaly/chemically induced/enzymology/physiopathology/*prevention & control
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - Genetic Predisposition to Disease
MH  - Lysine
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocardial Contraction/drug effects
MH  - Myocardium/*enzymology/pathology
MH  - Phenotype
MH  - Protein Binding
MH  - Protein Serine-Threonine Kinases/metabolism/pharmacology
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - Sirtuin 2/deficiency/genetics/*metabolism
MH  - Stroke Volume/drug effects
MH  - Ventricular Remodeling/drug effects
PMC - PMC5698109
MID - NIHMS911600
OTO - NOTNLM
OT  - AMPK
OT  - LKB1
OT  - SIRT2
OT  - aging
OT  - angiotensin II
OT  - cardiac hypertrophy
OT  - deacetylation
OT  - metformin
EDAT- 2017/09/28 06:00
MHDA- 2017/11/29 06:00
PMCR- 2018/11/21
CRDT- 2017/09/27 06:00
PHST- 2017/04/05 00:00 [received]
PHST- 2017/09/08 00:00 [accepted]
PHST- 2017/09/28 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/09/27 06:00 [entrez]
PHST- 2018/11/21 00:00 [pmc-release]
AID - CIRCULATIONAHA.117.028728 [pii]
AID - 10.1161/CIRCULATIONAHA.117.028728 [doi]
PST - ppublish
SO  - Circulation. 2017 Nov 21;136(21):2051-2067. doi: 
      10.1161/CIRCULATIONAHA.117.028728. Epub 2017 Sep 25.