Aldehyde Dehydrogenase 2 Protects Against Post-Cardiac Arrest Myocardial Dysfunction Through a Novel Mechanism of Suppressing Mitochondrial Reactive Oxygen Species Production

Zhang, Rui; Liu, Baoshan; Fan, Xiaoran; Wang, Wenjun; Xu, Tonghui; Wei, Shujian; Zheng, Wen; Yuan, Qiuhuan; Gao, Le; Yin, Xinxin; Zheng, Boyuan; Zhang, Chuanxin; Zhang, Shuai; Yang, Kehui; Xue, Mengyang; Wang, Shuo; Xu, Feng; Wang, Jiali; Cao, Yihai; Chen, Yuguo

doi:10.3389/fphar.2020.00373

Cited by 30 publications

(24 citation statements)

References 50 publications

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“…To understand the effect of ALDH2 activation on HS, Alda-1 was pretreated in HS induced HUVECs. Consistent with previous studies (29,31,48), Alda-1 (20mM) significantly augmented ALDH2 activity (Figure 3A) and reduced heat stress-induced ROS accumulation (Figures 3B, C). Alda-1 ameliorated the heat stress-induced cell death (Figure 3D) and reduced heat stressinduced apoptosis (Figure 3E) and senescence (Figure 3F) in HUVECs.…”

Section: Alda-1 Attenuates Heat Stress-induced Activation Of Inflammatory Pathways and Preserved Viability In Huvecs In Vitrosupporting

confidence: 92%

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: Alda-1 Attenuates Heat Stress-induced Activation Of Inflammatory Pathways and Preserved Viability In Huvecs In Vitrosupporting

confidence: 92%

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 can transform β-aminopropion-aldehyde to β-alanine [ 30 ] and is widely studied as an important cardioprotective factor [ 31 ]. Activate ALDH2 promote mitochondrial homeostasis and suppress mitochondrial ROS (reactive oxygen species) [ 32 , 33 ]. In our results, both MLYCD and ALDH2 was obviously up-regulated that MLYCD may a marker of ROS in central precocious puberty and ALDH2 may play an endogenous protective role.…”

Section: Discussionmentioning

confidence: 99%

The first central precocious puberty proteomic profiles revealed multiple metabolic networks and novel key disease-associated proteins

Wang

Chen

Yuan

et al. 2021

Aging

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“…The prototype of the ALDH2 activator, Alda-1, activated the wild type enzyme and restored the activity of the ALDH2*2 mutant enzyme by acting as a structural chaperone [29]. In a recent study, the activation of ALDH2 prevented the cardiac-arrest-induced death of cardiomyocytes from 4-HNE-induced mitochondrial ROS production and the subsequent mitochondrial damage and cell apoptosis [30]. In this study, we demonstrated that Alda-1 ameliorated 4-HNE-induced beta cell death, apoptosis, and mitochondrial, as well as cytoplasmic ROS levels.…”

Section: Discussionmentioning

confidence: 99%

Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

et al. 2021

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Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in Aldh2 knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.

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Aldehyde Dehydrogenase 2 Protects Against Post-Cardiac Arrest Myocardial Dysfunction Through a Novel Mechanism of Suppressing Mitochondrial Reactive Oxygen Species Production

Cited by 30 publications

References 50 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

The first central precocious puberty proteomic profiles revealed multiple metabolic networks and novel key disease-associated proteins

Activation of Aldehyde Dehydrogenase 2 Ameliorates Glucolipotoxicity of Pancreatic Beta Cells

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