Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells

Tsai, Shih‐Hung; Hsu, Lung‐An; Tsai, Hung-Chin; Yeh, Yung‐Hsin; Lu, Cheng-Yo; Chen, Po-Chuan; Wang, Jen-Chun; Chiu, Yi-Lin; Lin, Chih-Yuan; Hsu, Yu‐Juei

doi:10.1096/fj.201902550rrr

Cited by 25 publications

(25 citation statements)

References 75 publications

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“…Knock-in mice on a C57BL/6J background with an inactivating point mutation in ALDH2 (ALDH2*2) were generated by homologous recombination, as previously described ( 34 ). There were no significant phenotypic changes in ALDH2*2 KI mice.…”

Section: Methodsmentioning

confidence: 99%

“…After the 1-h heating period, the mice were returned to their home cages and given food and water ad libitum ( 40 ). These mice were treated with either vehicle control (20% DMSO and 20% PEG 400 in 100μl PBS) or Alda-1 [16 mg/kg in 100 μl in PBS with 20% DMSO and 20% PEG 400 (Sigma, 06855)] intraperitoneally 30 minutes prior to WBH as previously described with some modification ( 34 , 41 ). Previous literatures had showed that there were no obvious toxic or protective effects of this DMSO preparation on animal experiments ( 34 , 42 ).…”

Section: Methodsmentioning

confidence: 99%

“…The ALDH2 activator Alda-1 binds to ALDH2 and restores ALDH2 activity by acting as a structural chaperone (29). Previous studies indicated that Alda-1 attenuated the formation of 4-HNE protein adducts and inactivated the NF-kB pathway in several disease models (30)(31)(32)(33)(34). Pretreatment with Alda-1 had been shown to have beneficial effects on hyperoxia and acrolein induced ALI through preserving the endothelial barrier and mitochondrial dysfunction (35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

Tsai

Hsu

et al. 2021

Front. Immunol.

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Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

Tsai

Hsu

et al. 2021

Front. Immunol.

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“…ALDH2 is highly conserved in mice and humans. An ALDH2*2 KI mouse model on a C57BL/6J background with an inactivating point mutation in Aldh2 was generated using a CRISPR/CAS9 system as previously described [45]. In brief, to introduce a single nucleotide substitution (G to A) within exon 12 of the Aldh2 genomic fragment corresponding to the position of the human E487K mutation, three single guide RNAs (sgRNAs) were designed for a murine Aldh2 target locus, and their efficiencies were tested in cell lines.…”

Section: Generation Of Aldh2*2 Ki Mice Using Crispr/cas9mentioning

confidence: 99%

Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE

Hsu

Tsai

Yeh

et al. 2020

IJMS

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Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2, a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.

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“…MMPs released by macrophages damage elastic fibers and ECM, followed by more inflammatory cell recruitment to the injured site, which forms a vicious circle and eventually leads to either dilatation or rupture of AAA [36][37][38]. erefore, it is important to explore novel anti-inflammatory drugs that have been used in clinical AAA therapy [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

Chen

Han

Bian

et al. 2021

Journal of Oncology

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Chronic inflammation plays an essential role in the pathogenesis of abdominal aortic aneurysm (AAA), a progressive segmental abdominal aortic dilation. Chemerin, a multifunctional adipocytokine, is mainly generated in the liver and adipose tissue. The combination of chemerin and chemokine-like receptor 1 (CMKLR1) has been demonstrated to promote the progression of atherosclerosis, arthritis diseases, and Crohn’s disease. However, chemerin-9 acts as an analog of chemerin to exert an anti-inflammatory effect by binding to CMKLR1. Here, we first demonstrated that AAA exhibited higher levels of chemerin and CMKLR1 expression compared with the normal aortic tissues. Hence, we hypothesized that the chemerin/CMKLR1 axis might be involved in AAA progression. Moreover, we found that chemerin-9 treatment markedly suppressed inflammatory cell infiltration, neovascularization, and matrix metalloproteinase (MMP) expression, while increasing the elastic fibers and smooth muscle cells (SMCs) in Ang II-induced AAA in ApoE−/− mice. This demonstrated that chemerin-9 could inhibit AAA formation. Collectively, our findings indicate a potential mechanism underlying AAA progression and suggest that chemerin-9 can be used therapeutically.

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Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells

Cited by 25 publications

References 75 publications

Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE

Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

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