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ALDH1A3-mTOR Axis May be a Potential Target of Neurological Dysfunction after Deep Hypothermic Circulatory Arrest
Vol 38, Issue 2, 2024
Abstract
Background: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3)-mammalian target of rapamycin (mTOR) axis has been proven to be a therapeutic target for some tumors. We aimed to investigate the effect of ALDH1A3-mTOR axis on neurological dysfunction after deep hypothermic circulatory arrest (DHCA). Methods: Cardiopulmonary bypass (CPB) models were constructed using Sprague-Dawley (SD) rats, subjected to treatment with normal temperature circulatory arrest (NTCA) or DHCA, or pretreated with rapamycin, and their heart rate and breathing were monitored. The pathological damage of brain tissue was evaluated by hematoxylin and eosin staining. The expression of caveolin-1 (Cav-1) and nuclear factor-kappa B (NF-κB) was detected by quantitative real-time polymerase chain reaction. Oxygen glucose deprivation (OGD) cortical neurons model was employed, followed by treatment with hypothermia, MHY1485, or plasmid transfection as required. The effect of ALDH1A3-mTOR axis on OGD-induced neuronal activity and apoptosis in hypothermia state was detected by cell counting kit-8 (CCK-8) and flow cytometry. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS) level, and mTOR-70 kDa ribosomal protein S6 kinase (P70S6K) activation were determined by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe, and western blot. Results: Deep hypothermia reduced the heart rate and breathing of CPB rats. CPB aggravated tissue damage, reduced Cav-1 expression and MMP level, but increased ROS level and promoted NF-κB, ALDH1A3 expression and mTOR-P70S6K phosphorylation. Deep hypothermia slightly weakened the nerve damage induced by CPB. Rapamycin had shown a protective effect on the DHCA rat model. In the hypothermia state, silencing ALDH1A3 in vitro increased the cell viability and MMP inhibited by OGD, and reversed the apoptosis, ROS levels, ALDH1A3 expression, and activation of mTOR-P70S6K pathway. Conclusions: Silencing ALDH1A3 protects DHCA rats from nerve damage by inhibiting the mTOR-P70S6K pathway.
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Copyright (c) 2024 Jun Jiang, Hua Yang, Jun Chen, Pei Chen, Kuncheng Han, Yunchao Zhang, Wei Ni
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy