Abstract
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) gene encodes rate-limiting enzyme in cholesterol biosynthesis, which is related to cell proliferation and mitochondrial function. The present study was designed to explore the expression of HMGCR in murine cochlear hair cells and HEI-OC1 cells and the possible mechanisms underpinning the actions of HMGCR in cisplatin-induced ototoxicity, with special attention given to p38 mitogen-activated protein kinase (MAPK) activities in vitro. The expressions of HMGCR, p-p38, cleaved caspase-3 and LC3B was measured by immunofluorescence and western blot. JC-1 staining and MitoSOX Red were used to detect mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels respectively. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. Protein levels of bcl2/bax and beclin1 were examined by western blot. We found that HMGCR was widely expressed in the auditory cells, of both neonatal mice and 2-month-old mice, in cytoplasm, nucleus and stereocilia. Moreover, 30 μM cisplatin elicited the formation of ROS, which, in turn, led to HMGCR reduction, activating p38 kinase-related apoptosis and autophagy in auditory cells. Meanwhile, co-treatment with ROS scavenger at a concentration of 2 mM, N-acetyl-L-cysteine (NAC), could alleviate the aforementioned changes. In addition, HMGCR silencing resulted in higher p38 MAPK-mediated apoptosis and autophagy under cisplatin injury. Taken together, we demonstrate that, for the first time, that HMGCR is expressed in the cochlear. Furthermore, HMGCR exerts protective benefit on auditory cells against cisplatin-mediated injury stimulated by ROS, culminating in regulation of p38 MAPK-dependent apoptosis and autophagy.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.
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Acknowledgements
HEI-OC1 cell line was kindly provided by Qingyin Zheng, Department of Otolaryngology-HNS, Case Western Reserve University, Cleveland, OH, USA.
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This work was supported by the National Natural Science Foundation of China (Nos. 82071039; 82101215, 82201293).
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YL: conceived of or designed study, performed research and wrote the paper. HY, HN, FW and YW: contributed new methods or models. YX, JZ, HZ and ZC: analyzed data. QY: conceived of or designed study and revised the article. JL: conceived of or designed study, revised the article and approved the final version.
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Li, Y., Yang, H., Nong, H. et al. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) protects hair cells from cisplatin‐induced ototoxicity in vitro: possible relation to the activities of p38 MAPK signaling pathway. Arch Toxicol 97, 2955–2967 (2023). https://doi.org/10.1007/s00204-023-03588-z
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DOI: https://doi.org/10.1007/s00204-023-03588-z