Thrombosis and Haemostasis, Inhaltsverzeichnis

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‡^*

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

,

Qian Ren‡^*

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

,

Fanjie Zhang‡^*

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

,

Jing Gui

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

,

Xin Xiang

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

,

Qin Wan

¹Department of Endocrinology and Metabolism, Affiliated Hospital of Southwest Medical University, Luzhou, China

²Metabolic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, China

³Sichuan Clinical Research Center for Nephropathy, Luzhou, China

⁴Cardiovascular and Metabolic Diseases Key Laboratory of Luzhou, Luzhou, China

› Institutsangaben

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

Keywords

atherosclerosis - oxidative stress - diabetes mellitus

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