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ALDH2 activation attenuates oxygen–glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy

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Abstract

Purpose

It is previously reported that aldehyde dehydrogenase 2 family member (ALDH2) shows neuroprotective effects in cerebral ischemia/reperfusion injury. However, whether the protective effects are through mediating the programmed cell death is yet to be fully elucidated.

Methods

In vitro oxygen–glucose deprivation/reoxygenation (OGD/R) model was established in HT22 cells and mouse cortical neurons. Subsequently, ALDH2 expression were assessed by qRT-PCR and western blot. The methylation status was examined by methylation-specific PCR (MS-PCR). Then, ALDH2 expression was promoted and suppressed to explore the role of ALDH2 in OGD/R-treated cells. CCK-8 assay was applied to detect cell viability, and flow cytometry was applied to evaluate cell apoptosis. Western blot was applied to detect the apoptosis-related proteins (Caspase 3, Bcl-2 and Bax), necroptosis-related proteins (RIP3 and MLKL), pyroptosis-related proteins (NLRP3 and GSDMD), ferroptosis-related protein (ACSL4 and GPX4), and autophagy-related proteins (LC3B, and p62). IL-1β and IL-18 production was evaluated by ELISA assay. Reactive oxygen species production and Fe2+ content were evaluated by the corresponding detection kit.

Results

In OGD/R-treated cells, ALDH2 expression was decreased, which was due to the hypermethylation of ALDH2 in the promoter region. ALDH2 overexpression improved cell viability and ALDH2 knockdown suppressed cell viability in OGD/R-treated cells. We also found that ALDH2 overexpression attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy, while ALDH2 knockdown facilitated the OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy.

Conclusions

Collectively, our results implied that ALDH2 attenuated OGD/R-induced cell apoptosis, pyroptosis, ferroptosis and autophagy to promote cell viability in HT22 cells and mouse cortical neurons.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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  1. Department of Emergency, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, Shandong, China

    Yun Qu & Yuanyuan Liu

  2. Department of Neurology, Yuhuangding Hospital Affiliated to Qingdao University, No. 20 Yudong Road, Zhifu District, Yantai, 264000, Shandong, China

    Huilong Zhang

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YQ, YYL and HLZ contributed to research conception and design as well as manuscript drafting; YQ, YYL analyzed and interpreted data; YQ, YYL and HLZ made statistical analysis; YQ, YYL and HLZ revised the manuscript; In addition, all authors approved final manuscript.

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Qu, Y., Liu, Y. & Zhang, H. ALDH2 activation attenuates oxygen–glucose deprivation/reoxygenation-induced cell apoptosis, pyroptosis, ferroptosis and autophagy. Clin Transl Oncol 25, 3203–3216 (2023). https://doi.org/10.1007/s12094-023-03190-w

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