Knockdown of FXYD2 inhibits mepivacaine-induced cardiomyocyte injury by activating the PI3K/AKT signaling pathway.

BACKGROUND: Myocardial infarction (MI) is a severe cardiovascular event associated with various molecular alterations. This study aimed to explore the intricate relationship between mepivacaine, a local anesthetic, and MI by identifying and characterizing overlapping genes through a comprehensive analysis. METHODS: Differential expression analysis was performed using the GSE19339 data set to identify overlapping genes between MI and mepivacaine, and functional enrichment analysis as well as expression verification was performed. Rat cardiomyocyte H9c2 cells were divided into four groups: control, a model group (mepivacaine), treatment (si-FXYD2 + mepivacaine) and PI3K inhibitor group (si-FXYD2 + mepivacaine + LY294002). In vitro analysis of the effects of FXYD2 regulation on the viability, of Lactate dehydrogenase (LDH) release, Reactive oxygen species (ROS) generation, PI3K/AKT signaling pathway activation, oxidative stress, apoptosis, mitochondrial respiratory chain activity, and endoplasmic reticulum (ER) stress of mepivacaine-treated H9c2 cells. RESULTS: Eight genes were identified linking MI to mepivacaine, with FXYD2 notably upregulated in MI samples. In vitro experiments confirmed that FXYD2 knockdown in H9c2 cells significantly alleviated the mepivacaine-induced decrease in cell viability and oxidative stress, as well as the increase in apoptosis (p < 0.05). Knocking down FXYD2 inhibits mepivacaine-induced mitochondrial damage, effectively alleviates endoplasmic reticulum stress under mepivacaine treatment, and reduces the expression of stress markers (GRP78, CHOP). These cellular protections are mediated through the PI3K/AKT signaling pathway, whose activation is modulated by FXYD2 expression and mepivacaine treatment (p < 0.05). CONCLUSIONS: Knockdown of FXYD2 plays a key role in reducing mepivacaine-induced cardiomyocyte injury by modulating oxidative stress, apoptosis, mitochondrial function, and ER stress, mediated through the PI3K/AKT signaling cascade.