Unraveling the role of LDHA and VEGFA in oxidative stress: A pathway to therapeutic interventions in cerebral...

Area of Science:

• Biochemistry
• Molecular Biology
• Vascular Biology

Background:

• Cerebral aneurysms (CA) are linked to oxidative stress in vascular endothelial cells (VECs).
• Lactate dehydrogenase A (LDHA) and glycolysis are implicated in aneurysm pathogenesis.
• Understanding these pathways is key for novel therapeutic targets.

Purpose of the Study:

• Investigate lactate metabolism and related genes (LDHA, VEGFA) in VECs under oxidative stress.
• Determine the role of LDHA and VEGFA in VEC response to oxidative stress and OGD/R.
• Evaluate the therapeutic potential of targeting glycolysis in CA.

Main Methods:

• Bioinformatic analysis of GSE26969 dataset for differential gene expression.
• In vitro induction of oxidative stress in VECs using H2O2.
• qRT-PCR and Western Blotting for gene and protein expression analysis.
• Assessment of cell viability and apoptosis under OGD/R with LDHA overexpression and VEGFA knockdown.
• Immunoprecipitation to detect LDHA lactylation.

Main Results:

• Oxidative stress shifts VEC metabolism towards glycolysis, increasing LDHA expression, glucose uptake, and lactate production.
• LDHA overexpression enhanced VEC survival and reduced apoptosis.
• VEGFA knockdown exacerbated apoptosis.
• 2-deoxyglucose (2-DG) treatment decreased LDHA lactylation and apoptosis.

Conclusions:

• LDHA is critical for VEC response to oxidative stress, playing a protective role.
• Targeting glycolysis through LDHA modulation offers a potential therapeutic strategy for CA.
• This study advances understanding of metabolic adaptations in vascular diseases and CA management.