LDHA enhances brain injury and apoptosis after intracerebral hemorrhage by promoting P53 transcription through increasing P53 lactylation.

Abstract

Intracerebral hemorrhage(ICH) is a cerebrovascular disease with high disability and fatality rate, and inhibition of neuronal cell death is the key to improve ICH injury. Histone lactylation is induced by lactate, it role in ICH remains unclear. P53 plays a key role in apoptosis. This study aims to investigate the role of lactate dehydrogenase A(LDHA), a key factor in the production of lactate, in the development of ICH and its regulation of P53. In vitro and in vivo ICH model was construct by stimulation of hemin on PC12 cells and collagenase IV injection in C57BL/6J mice. Lactate production was detected using a lactate kit. LDHA and P53 expression was measured by quantitative real-time PCR. Western blot was performed to detect the protein level of pan-kla, apoptosis-related factors and histone lactylation. Impact of LDHA in ICH was evaluated by measuring cell viability, proliferation, apoptosis, neurobehavioral function assessment and pathological observation. Results showed that lactate production, LDHA expression and histone lactylation were increased after ICH. LDHA knockdown promoted cell viability and proliferation but suppressed apoptosis after ICH in vitro, and improved neurological function, brain injury and apoptosis after ICH in vivo. Mechanically, LDHA knockdown inhibited P53 transcription by decreasing lactylation on P53 promoter. Moreover, P53 overexpression restored apoptosis and brain injury after ICH improved by LDHA knockdown. In conclusion, we demonstrated that LDHA enhanced brain injury and apoptosis after ICH by promoting P53 transcription through increasing lactylation on P53 promoter. These results may provide a novel therapeutic target for ICH injury.