LDHA protects vascular endothelial cells from oxidative stress‑induced mitochondrial damage via HIF‑1α activation and glycolytic reprogramming

Oxidative stress‑induced damage contributes to endothelial dysfunction, a key feature in the pathogenesis of cerebral aneurysms (CAs). Lactate dehydrogenase A (LDHA) serves a crucial role in regulating metabolic adaptation under stress. The present study aimed to explore the protective effects of LDHA overexpression on vascular endothelial cells (VECs) under oxidative stress induced by hydrogen peroxide (H2O2). VECs were exposed to 0.5 mM H2O2 in an oxygen‑glucose deprivation/reperfusion (OGD/R) model to induce oxidative stress, mimicking conditions relevant to CA. LDHA overexpression was achieved using a plasmid vector. Subsequently, western blotting, flow cytometry, reverse transcription‑quantitative polymerase chain reaction, transmission electron microscopy and JC‑1 staining were used to assess apoptosis, mitochondrial function, glycolysis and oxidative stress markers. Extracellular acidification rate was measured to evaluate glycolytic activity. The results revealed that LDHA overexpression reduced oxidative stress‑induced apoptosis and mitochondrial damage in VECs, as evidenced by decreased caspase activation (caspase‑3, caspase‑9), preserved mitochondrial structure and improved mitochondrial membrane potential. Additionally, LDHA overexpression mitigated reactive oxygen species production and activated hypoxia‑inducible factor 1α (HIF‑1α). It also increased the expression of glycolytic genes (hexokinase 2, phosphoglucomutase 5 and pyruvate kinase M) and upregulated the lactate transporter monocarboxylate transporter 4, while decreasing succinate levels. Furthermore, LDHA overexpression enhanced NADPH levels and glucose‑6‑phosphate dehydrogenase activity, indicating the activation of the pentose phosphate pathway to maintain redox balance. In conclusion, LDHA may protect VECs from mitochondrial dysfunction and oxidative damage in the context of CA by enhancing glycolytic metabolism and HIF‑1α signaling. LDHA could therefore serve as a possible therapeutic target for the treatment and prevention of CAs.