Suppressive effects of lovastatin on OGD/hemin-induced inflammation and ferroptosis in brain microvascular endothelial cells through the METTL3/HDAC6 cascade.
Xiaolong Wang, Liangsheng Peng, Li Han, Yuanzhao Tuo, Huahui Chen, Xuemin Wang, Lixiong Xue, Xinmin Ding
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引用次数: 0
Abstract
Background: Intracerebral hemorrhage (ICH) induces dysfunction in brain microvascular endothelial cells (BMVECs), thereby contributing to secondary brain injuries. Emerging evidence implicates METTL3 and HDAC6 as critical mediators of inflammation and ferroptosis that contribute to post-ICH neurological impairment. Lovastatin exhibits anti-inflammatory, anti-oxidative, and neuroprotective properties. This study elucidated the therapeutic potential of lovastatin in attenuating BMVEC injury following ICH, while investigating the mechanistic involvement of METTL3 and HDAC6 in this protective process.
Methods: The cell damage model following ICH was generated by stimulating human BMVECs with oxygen and glucose deprivation (OGD) and hemin (OGD/H). Cell impairment was assessed by detecting permeability. Cell viability, migration, tube formation, and apoptosis were evaluated by CCK-8, transwell, tube formation, and flow cytometry analyses, respectively. TNF-α and IL-6 levels were detected by ELISA. Cell ferroptosis was analyzed by assessing related factor expression. Methylated RNA immunoprecipitation (MeRIP), RIP, quantitative PCR, and actinomycin D treatment assays were used to test the METTL3/histone deacetylase 6 (HDAC6) relationship.
Results: Lovastatin protected BMVECs from OGD/H-evoked dysfunction. Moreover, lovastatin relieved OGD/H-evoked oxidative stress, inflammation, and ferroptosis in BMVECs. Mechanistically, the potential docking poses of lovastatin with METTL3 were predicted, and METTL3 stabilized HDAC6 mRNA through mRNA m6A modification. Lovastatin reduced METTL3 and HDAC6 levels in OGD/H-stimulated human BMVECs, and lovastatin decreased HDAC6 expression by downregulating METTL3. Furthermore, lovastatin alleviated OGD/H-induced BMVEC impairment, inflammation and ferroptosis by the METTL3/HDAC6 cascade.
Conclusion: Our study demonstrates that lovastatin suppresses OGD/H-induced inflammation and ferroptosis in human BMVECs through the potential METTL3/HDAC6 cascade, providing novel evidence for the neuroprotective role of lovastatin.
期刊介绍：
SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.
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