Free radical biology & medicine · 2026
OX-LDL causes vascular endothelial injury by interfering with the CREB1-MDH1B-malate axis.
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Pu Chen, Yang Hailang, Wang Guorong, Wang Xueting, Wan Xiaobin, Liu Qiang, Zhao Yanping
Аннотация
BACKGROUND: Atherosclerosis (AS) is one of the most prevalent cardiovascular disorders, with endothelial dysfunction recognized as a central initiating event in its pathogenesis. Oxidized low-density lipoprotein (ox-LDL) is a key pathogenic factor that contributes to vascular injury. While the pro-atherogenic and oxidative effects of ox-LDL have been well described, the mechanisms by which it influences cellular energy metabolism remain largely unclear.
OBJECTIVE: This study aims to elucidate how ox-LDL impairs endothelial cell function through repression of the transcription factor CREB1 and its downstream target gene MDH1B, leading to disrupted malate metabolism and mitochondrial dysfunction. These findings are intended to provide mechanistic insights and identify potential targets for therapeutic intervention in vascular injury.
METHODS: Differentially expressed genes were identified by analyzing the GSE13139 dataset, and candidate genes were validated in human aortic endothelial cells (HAECs). The transcriptional regulation of MDH1B by CREB1 was investigated using RT-qPCR, Western blotting, dual-luciferase reporter assays, and ChIP-qPCR. Malate, ATP, and ADP levels were measured alongside mitochondrial membrane potential (JC-1 staining) and ultrastructural analyses by transmission electron microscopy. Functional relevance was validated in high-cholesterol diet mouse models.
RESULTS: Ox-LDL suppressed CREB1 expression, phosphorylation, and nuclear translocation, resulting in downregulation of MDH1B. This repression impaired malate production, reduced mitochondrial membrane potential, and decreased ATP levels in endothelial cells. MDH1B overexpression restored malate levels, improved mitochondrial function, and attenuated ox-LDL-induced endothelial injury. Exogenous malate supplementation partially rescued metabolic deficits and cellular viability but did not restore the CREB1-MDH1B axis.
CONCLUSION: This study reveals that ox-LDL impairs endothelial function by inhibiting CREB1 phosphorylation/nuclear translocation, which suppresses MDH1B transcription. This disrupts malate metabolism, causing mitochondrial dysfunction and endothelial injury. The CREB1-MDH1B-malate axis bridges transcriptional regulation with metabolic homeostasis, offering a potential therapeutic target for ox-LDL-induced vascular injury.
OBJECTIVE: This study aims to elucidate how ox-LDL impairs endothelial cell function through repression of the transcription factor CREB1 and its downstream target gene MDH1B, leading to disrupted malate metabolism and mitochondrial dysfunction. These findings are intended to provide mechanistic insights and identify potential targets for therapeutic intervention in vascular injury.
METHODS: Differentially expressed genes were identified by analyzing the GSE13139 dataset, and candidate genes were validated in human aortic endothelial cells (HAECs). The transcriptional regulation of MDH1B by CREB1 was investigated using RT-qPCR, Western blotting, dual-luciferase reporter assays, and ChIP-qPCR. Malate, ATP, and ADP levels were measured alongside mitochondrial membrane potential (JC-1 staining) and ultrastructural analyses by transmission electron microscopy. Functional relevance was validated in high-cholesterol diet mouse models.
RESULTS: Ox-LDL suppressed CREB1 expression, phosphorylation, and nuclear translocation, resulting in downregulation of MDH1B. This repression impaired malate production, reduced mitochondrial membrane potential, and decreased ATP levels in endothelial cells. MDH1B overexpression restored malate levels, improved mitochondrial function, and attenuated ox-LDL-induced endothelial injury. Exogenous malate supplementation partially rescued metabolic deficits and cellular viability but did not restore the CREB1-MDH1B axis.
CONCLUSION: This study reveals that ox-LDL impairs endothelial function by inhibiting CREB1 phosphorylation/nuclear translocation, which suppresses MDH1B transcription. This disrupts malate metabolism, causing mitochondrial dysfunction and endothelial injury. The CREB1-MDH1B-malate axis bridges transcriptional regulation with metabolic homeostasis, offering a potential therapeutic target for ox-LDL-induced vascular injury.