The role of aldehyde dehydrogenase 2 in cardiovascular disease

Zhang, Jian; Guo, Yunyun; Zhao, Xiangkai; Pang, Jiaojiao; Pan, Chang; Wang, Jiali; Wei, Shujian; Yu, Xiao; Zhang, Cheng; Chen, Yuguo; Yin, Huiyong; Xu, Feng

doi:10.1038/s41569-023-00839-5

Cited by 57 publications

(21 citation statements)

References 170 publications

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“…Many studies have suggested that ALDH2 exerts beneficial effects by clearing 4-HNE. 18,51 However, no ideal ALDH2 activator has been applied 4-HNE indicates 4-hydroxynonenal; ALDH2, aldehyde dehydrogenase 2; α-SMA, α smooth muscle actin; BMP2, bone morphogenetic protein 2; MSX2, msh homeobox 2; OPN, osteopontin; Runx2, runt-related transcription factor-2; SM22α, smooth muscle 22 α; and VSMC, vascular smooth muscle cell.…”

Section: Discussionmentioning

confidence: 99%

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

Zhai,

Cao,

Wang

et al. 2024

Circulation

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BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2 -/- ) mice, smooth muscle cell–specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing β-glycerophosphate and CaCl 2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell–specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE–induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

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Section: Discussionmentioning

confidence: 99%

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

Zhai,

Cao,

Wang

et al. 2024

Circulation

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“…MDSC is an anti-inflammatory immune cell characterized by CD11b and Gr-1 expression. It inhibits T-cell activity through hydrogen peroxide, thereby reducing the number and pro-inflammatory phenotype of inflammatory cells in the spleen and kidneys, further regulating the immune system and hypertension ( Zhang et al, 2023b ). However, there are relatively few reports on the correlation between ALDH2 and these immune cells.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the molecular mechanism of Smilax glabra Roxb. in treating hypertension based on proteomics and bioinformatics

Yang,

Qian,

Yang

et al. 2024

Front. Pharmacol.

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BackgroundSmilax glabra Roxb. (named tufuling in Chinese, SGR) has both medicinal and edible value. SGR has obvious pharmacological activity, especially in anti-inflammation and treating immune system diseases. This study investigated differential protein expression and its relationship with immune infiltration in hypertension treated with SGR using proteomics and bioinformatics.MethodsN-Nitro L-arginine methyl ester (L-NAME) was used to replicate the hypertension model, with SGR administered by gavage for 4 weeks, and the systolic and diastolic blood pressure in each group of rats was measured using the tail-cuff method every 7 days. Furthermore, enzyme-linked immunosorbent assay (ELISA) was used to determine the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) expressions in each group, followed by the detection of protein expression in rat liver samples using the tandem mass tag (TMT) technique. Additionally, hub targets were output using Cytoscape 3.9.1 software, and ALDH2 expression in the liver and serum in each group of rats was detected by ELISA. Moreover, R4.3.0 software was used to evaluate the relationship between acetaldehyde dehydrogenase 2 (ALDH2) and immune cells, and ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) was performed to identify the components of SGR. Furthermore, the association between components of SGR and ALDH2 was analyzed with molecular docking and LigPlot1.4.5 software.ResultsCompared with the model group (L-NAME), SGR at high and medium doses reduced systolic and diastolic blood pressure while reducing TC, TG, and LDL-C levels and increasing HDL-C levels in hypertensive rats (p < 0.05). Moreover, 92 differentially expressed proteins (DEPs) were identified using TMT. These DEPs participated in peroxisome functioning, fatty acid degradation, and other signaling pathways, with ALDH2 being the core target and correlated with various immune cells. In addition, 18 components were determined in SGR, with 8 compounds binding to ALDH2. Molecular docking was performed to confirm that SGR played a role in hypertension based on the combined action of multiple components.ConclusionIn conclusion, SGR has an antihypertensive effect on L-NAME-induced hypertension, with ALDH2 as its hub target. SGR may regulate neutrophil, regulatory T cell, and other cells’ infiltration by targeting ALDH2, thereby contributing to the treatment of hypertension.

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“…There are challenges to be overcome in the translational relevance of ALDH2: 1) ALDH2 has mainly protective roles in the heart and the cardiac vasculature, and we propose a tissuespecific strategy of ALDH2 inhibition to improve risk management of cardiovascular disease. [29,52,53] Patients with a high risk of developing AAA as opposed to ischemic heart disease (IHD) may likely benefit more from ALDH2 inhibition. On the other hand, ALDH2 inhibition may not be the best option for AAA patients with known IHD.…”

Section: Discussionmentioning

confidence: 99%

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2‐LIN28B‐ELK3 Signaling

Yang,

Cui,

Wang

et al. 2023

Advanced Science

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The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single‐cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)‐induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier‐related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early‐stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post‐Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2‐specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

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The role of aldehyde dehydrogenase 2 in cardiovascular disease

Cited by 57 publications

References 170 publications

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

Investigation of the molecular mechanism of Smilax glabra Roxb. in treating hypertension based on proteomics and bioinformatics

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2‐LIN28B‐ELK3 Signaling

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