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Thromb Haemost 2023; 123(10): 1003-1015
DOI: 10.1055/s-0043-1770985
Atherosclerosis and Ischaemic Disease

D-β-Hydroxybutyrate Dehydrogenase Mitigates Diabetes-Induced Atherosclerosis through the Activation of Nrf2

Jie Lin‡   *
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
,
Qian Ren‡   *
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
,
Fanjie Zhang‡   *
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
,
Jing Gui
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
,
Xin Xiang
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
,
Qin Wan 
1   Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China
2   Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China
3   Sichuan Clinical Research Center for Nephropathy, Luzhou, China
4   Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China
› Author Affiliations Funding This research was funded by the Ministry of Science and Technology of China (grant number: 2016YFC0901200), Luzhou Science and Technology Bureau (grant number: 2021-JYJ-64), and Key Research and Development Program of Science and Technology Department of Sichuan Province (grant number: 2022YFS0612).
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Abstract

Background We aimed to investigate the role and mechanism of β-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.

Keywords

atherosclerosis - oxidative stress - diabetes mellitus

Data Availability Statement

All data generated or analyzed during this study are included in this published article.


Ethics Approval Statement

This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Southwest Medical University Hospital (protocol code: 20211122). The Southwest Medical University Institutional Animal Ethics Committee approved the animal protocol of this study (protocol code: 20211119–046). All the study participants provided informed consent.


Authors' Contribution

All authors reviewed the manuscript, participated in the discussion, and approved the final manuscript. J.L., Q.R., and F.Z. equally contributed to this work, performed statistical analyses, interpreted the results, and wrote the paper. J.G. and X.X. reviewed the data, and Q.W. proposed the idea. All the authors contributed to the manuscript and approved the submitted version.


* These authors equally contributed to this work and are joint first authors.


Supplementary Material



Publication History

Received: 03 December 2022

Accepted: 01 June 2023

Article published online:
03 July 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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