PMID- 30315930
OWN - NLM
STAT- MEDLINE
DCOM- 20200304
LR  - 20200304
IS  - 1879-260X (Electronic)
IS  - 0925-4439 (Linking)
VI  - 1865
IP  - 7
DP  - 2019 Jul 1
TI  - Aldehyde dehydrogenase 2 deficiency promotes atherosclerotic plaque instability 
      through accelerating mitochondrial ROS-mediated vascular smooth muscle cell 
      senescence.
PG  - 1782-1792
LID - S0925-4439(18)30376-4 [pii]
LID - 10.1016/j.bbadis.2018.09.033 [doi]
AB  - Previous evidence has indicated a beneficial role for aldehyde dehydrogenase 2 
      (ALDH2) in suppressing atherosclerotic plaque progression and instability. 
      However, the underlying mechanism remains somewhat elusive. This study was 
      designed to examine the effect of ALDH2 deficiency on high-cholesterol 
      diet-induced atherosclerotic plaque progression and plaque vulnerability in 
      atherosclerosis-prone ApoE knockout (ApoE(-/-)) mice with a focus on foam cell 
      formation in macrophages and senescence of vascular smooth muscle cells (VSMCs). 
      Serum lipid profile, plaque progression, and plaque vulnerability were examined 
      in ApoE(-/-) and ALDH2/ApoE double knockout (ALDH2(-/-)ApoE(-/-)) mice after 
      high-cholesterol diet intake for 8 weeks. ALDH2 deficiency increased the serum 
      levels of triglycerides while it decreased levels of total cholesterol and 
      high-density lipoprotein cholesterol. Unexpectedly, ALDH2 deficiency reduced the 
      plaque area by 58.9% and 37.5% in aorta and aortic sinus, respectively. Plaque 
      instability was aggravated by ALDH2 deficiency along with the increased necrotic 
      core size, decreased collagen content, thinner fibrous cap area, decreased VSMC 
      content, and increased macrophage content. In atherosclerotic lesions, ALDH2 
      protein was located in both macrophages and VSMCs. Further results revealed 
      downregulated ALDH2 expression in aorta of aged ApoE(-/-) mice compared with 
      young mice. However, in vitro study suggested that ALDH2 expression was 
      upregulated in bone marrow-derived macrophages (BMDMs) with an opposite effect in 
      VSMCs following 80 mug/ml oxidized low-density lipoprotein (oxLDL) treatment. 
      Interestingly, ALDH2 deficiency displayed little effect in oxLDL-induced foam 
      cell formation from BMDMs, while ALDH2 knockdown by siRNA and ALDH2 
      overexpression by lentivirus infection promoted and retarded oxLDL-induced VSMC 
      senescence, respectively. Mechanistically, ALDH2 mitigated oxLDL-induced 
      overproduction of mitochondrial reactive oxygen species (mROS) and activation of 
      downstream p53/p21/p16 pathway. Clearance of mROS by mitoTEMPO significantly 
      reversed the promotive effect of ALDH2 knockdown on VSMC senescence. Taken 
      together, our data revealed that ALDH2 deficiency suppressed atherosclerotic 
      plaque area while facilitating plaque instability possibly through accelerating 
      mROS-mediated VSMC senescence. This article is part of a Special Issue entitled: 
      Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & 
      Megan Yingmei Zhang.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Zhu, Hong
AU  - Zhu H
AD  - Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital & Institute of 
      Biomedical Sciences, Fudan University, Shanghai 200032, China.
FAU - Wang, Zeng
AU  - Wang Z
AD  - Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital & Institute of 
      Biomedical Sciences, Fudan University, Shanghai 200032, China.
FAU - Dong, Zhen
AU  - Dong Z
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Wang, Cong
AU  - Wang C
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Cao, Quan
AU  - Cao Q
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Fan, Fan
AU  - Fan F
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Zhao, Jingjing
AU  - Zhao J
AD  - Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, 
      Guangzhou 510080, China.
FAU - Liu, Xiangwei
AU  - Liu X
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Yuan, Meng
AU  - Yuan M
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Sun, Xiaolei
AU  - Sun X
AD  - Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital & Institute of 
      Biomedical Sciences, Fudan University, Shanghai 200032, China.
FAU - Peng, Xiuhua
AU  - Peng X
AD  - Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China.
FAU - Zou, Yunzeng
AU  - Zou Y
AD  - Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital & Institute of 
      Biomedical Sciences, Fudan University, Shanghai 200032, China.
FAU - Zhou, Jingmin
AU  - Zhou J
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China.
FAU - Ge, Junbo
AU  - Ge J
AD  - Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital & Institute of 
      Biomedical Sciences, Fudan University, Shanghai 200032, China.
FAU - Zhou, Xiaohui
AU  - Zhou X
AD  - Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China. 
      Electronic address: zhouxiaohui@shphc.org.cn.
FAU - Zhang, Yingmei
AU  - Zhang Y
AD  - Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, 
      Zhongshan Hospital, Fudan University Shanghai 200032, China. Electronic address: 
      zhang.yingmei@zs-hospital.sh.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181011
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Basis Dis
JT  - Biochimica et biophysica acta. Molecular basis of disease
JID - 101731730
RN  - 0 (Apolipoproteins E)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.2.1.3 (ALDH2 protein, mouse)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase, Mitochondrial)
SB  - IM
MH  - Aldehyde Dehydrogenase, Mitochondrial/*genetics/metabolism
MH  - Animals
MH  - Apolipoproteins E/genetics
MH  - Cellular Senescence
MH  - Gene Deletion
MH  - Gene Knockdown Techniques
MH  - Mice, Inbred C57BL
MH  - Mitochondria/genetics/metabolism/pathology
MH  - Muscle, Smooth, Vascular/metabolism/*pathology
MH  - Plaque, Atherosclerotic/genetics/*pathology
MH  - Reactive Oxygen Species/*metabolism
OTO - NOTNLM
OT  - ALDH2
OT  - Atherosclerosis
OT  - Macrophage
OT  - Mitochondrial ROS
OT  - Senescence
OT  - VSMC
EDAT- 2018/10/14 06:00
MHDA- 2020/03/05 06:00
CRDT- 2018/10/14 06:00
PHST- 2018/07/31 00:00 [received]
PHST- 2018/09/26 00:00 [revised]
PHST- 2018/09/27 00:00 [accepted]
PHST- 2018/10/14 06:00 [pubmed]
PHST- 2020/03/05 06:00 [medline]
PHST- 2018/10/14 06:00 [entrez]
AID - S0925-4439(18)30376-4 [pii]
AID - 10.1016/j.bbadis.2018.09.033 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Basis Dis. 2019 Jul 1;1865(7):1782-1792. doi: 
      10.1016/j.bbadis.2018.09.033. Epub 2018 Oct 11.