PMID- 37399841
OWN - NLM
STAT- MEDLINE
DCOM- 20230928
LR  - 20230928
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 123
IP  - 10
DP  - 2023 Oct
TI  - D-beta-Hydroxybutyrate Dehydrogenase Mitigates Diabetes-Induced Atherosclerosis 
      through the Activation of Nrf2.
PG  - 1003-1015
LID - 10.1055/s-0043-1770985 [doi]
AB  - BACKGROUND:  We aimed to investigate the role and mechanism of beta-hydroxybutyrate 
      dehydrogenase 1 (Bdh1) in regulating macrophage oxidative stress in 
      diabetes-induced atherosclerosis (AS). METHODS:  We performed immunohistochemical 
      analysis of femoral artery sections to determine differences in Bdh1 expression 
      between normal participants, AS patients, and patients with diabetes-induced AS. 
      Diabetic Apoe-/- mice and high-glucose (HG)-treated Raw264.7 macrophages were 
      used to replicate the diabetes-induced AS model. The role of Bdh1 in this disease 
      model was determined by adeno-associated virus (AAV)-mediated overexpression of 
      Bdh1 or overexpression or silencing of Bdh1. RESULTS:  We observed reduced 
      expression of Bdh1 in patients with diabetes-induced AS, HG-treated macrophages, 
      and diabetic Apoe-/- mice. AAV-mediated Bdh1 overexpression attenuated aortic 
      plaque formation in diabetic Apoe-/- mice. Silencing of Bdh1 resulted in 
      increased reactive oxygen species (ROS) production and an inflammatory response 
      in macrophages, which were reversed by the ROS scavenger N-acetylcysteine. 
      Overexpression of Bdh1 protected Raw264.7 cells from HG-induced cytotoxicity by 
      inhibiting ROS overproduction. In addition, Bdh1 induced oxidative stress through 
      nuclear factor erythroid-related factor 2 (Nrf2) activation by fumarate acid. 
      CONCLUSION:  Bdh1 attenuates AS in Apoe-/- mice with type 2 diabetes, accelerates 
      lipid degradation, and reduces lipid levels by promoting ketone body metabolism. 
      Moreover, it activates the Nrf2 pathway of Raw264.7 by regulating the metabolic 
      flux of fumarate, which inhibits oxidative stress and leads to a decrease in ROS 
      and inflammatory factor production.
CI  - Thieme. All rights reserved.
FAU - Lin, Jie
AU  - Lin J
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
FAU - Ren, Qian
AU  - Ren Q
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
FAU - Zhang, Fanjie
AU  - Zhang F
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
FAU - Gui, Jing
AU  - Gui J
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
FAU - Xiang, Xin
AU  - Xiang X
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
FAU - Wan, Qin
AU  - Wan Q
AUID- ORCID: 0000-0001-7765-1416
AD  - Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest 
      Medical University, Luzhou, China.
AD  - Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China.
AD  - Sichuan Clinical Research Center for Nephropathy, Luzhou, China.
AD  - Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China.
LA  - eng
GR  - 2016YFC0901200/Ministry of Science and Technology of China/
GR  - 2021-JYJ-64/Luzhou Science and Technology Bureau/
GR  - 2022YFS0612/Key Research and Development Program of Science and Technology 
      Department of Sichuan Province/
PT  - Journal Article
DEP - 20230703
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - EC 1.1.1.30 (Hydroxybutyrate Dehydrogenase)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Fumarates)
RN  - 0 (Lipids)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - Hydroxybutyrate Dehydrogenase/metabolism
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - *Diabetes Mellitus, Type 2/complications/metabolism
MH  - Reactive Oxygen Species
MH  - Mice, Knockout, ApoE
MH  - *Atherosclerosis/genetics/prevention & control
MH  - Oxidative Stress
MH  - Apolipoproteins E
MH  - Fumarates
MH  - Lipids
COIS- None declared.
EDAT- 2023/07/04 01:05
MHDA- 2023/09/28 06:42
CRDT- 2023/07/03 19:13
PHST- 2023/09/28 06:42 [medline]
PHST- 2023/07/04 01:05 [pubmed]
PHST- 2023/07/03 19:13 [entrez]
AID - 10.1055/s-0043-1770985 [doi]
PST - ppublish
SO  - Thromb Haemost. 2023 Oct;123(10):1003-1015. doi: 10.1055/s-0043-1770985. Epub 
      2023 Jul 3.